U.S. patent application number 13/491053 was filed with the patent office on 2012-10-18 for multi-functional ionic liquid compositions for overcoming polymorphism and imparting improved properties for active pharmaceutical, biological, nutritional, and energetic ingredients.
This patent application is currently assigned to THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ALABAMA. Invention is credited to Daniel T. Daly, James Hilliard Davis, JR., Whitney L. Hough-Troutman, Juliusz Pernak, Robin D. Rogers, Marcin Smiglak, Scott K. Spear, Richard P. Swatloski.
Application Number | 20120264605 13/491053 |
Document ID | / |
Family ID | 37943465 |
Filed Date | 2012-10-18 |
United States Patent
Application |
20120264605 |
Kind Code |
A1 |
Rogers; Robin D. ; et
al. |
October 18, 2012 |
Multi-Functional Ionic Liquid Compositions for Overcoming
Polymorphism and Imparting Improved Properties for Active
Pharmaceutical, Biological, Nutritional, and Energetic
Ingredients
Abstract
Disclosed are ionic liquids and methods of preparing ionic
liquid compositions of active pharmaceutical, biological,
nutritional, and energetic ingredients. Also disclosed are methods
of using the compositions described herein to overcome
polymorphism, overcome solubility and delivery problems, to control
release rates, add functionality, enhance efficacy (synergy), and
improve ease of use and manufacture.
Inventors: |
Rogers; Robin D.;
(Tuscaloosa, AL) ; Daly; Daniel T.; (Tuscaloosa,
AL) ; Swatloski; Richard P.; (Tuscaloosa, AL)
; Hough-Troutman; Whitney L.; (Tuscaloosa, AL) ;
Davis, JR.; James Hilliard; (Mobile, AL) ; Smiglak;
Marcin; (Tuscaloosa, AL) ; Pernak; Juliusz;
(Pozan, PL) ; Spear; Scott K.; (Bankston,
AL) |
Assignee: |
THE BOARD OF TRUSTEES OF THE
UNIVERSITY OF ALABAMA
Tuscaloosa
AL
|
Family ID: |
37943465 |
Appl. No.: |
13/491053 |
Filed: |
June 7, 2012 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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11545938 |
Oct 10, 2006 |
8232265 |
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13491053 |
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60764850 |
Feb 2, 2006 |
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60724604 |
Oct 7, 2005 |
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60724605 |
Oct 7, 2005 |
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Current U.S.
Class: |
504/206 ;
504/234; 504/238; 504/273; 504/302; 504/324; 504/347; 544/204;
544/224; 548/263.2; 560/12; 562/473; 562/575; 564/441 |
Current CPC
Class: |
A61K 31/341 20130101;
A61K 31/28 20130101; A61P 17/16 20180101; A61P 31/00 20180101; A61K
31/496 20130101; A61K 31/60 20130101; A61K 31/14 20130101; A61P
23/00 20180101; A61K 31/167 20130101; A61K 31/19 20130101; A61K
9/143 20130101; A61K 31/4174 20130101; A61K 31/305 20130101; A61K
31/496 20130101; A61K 31/635 20130101; A61P 31/04 20180101; A61K
31/167 20130101; A61K 31/451 20130101; A61K 31/465 20130101; A61K
31/5415 20130101; A61K 31/7036 20130101; A61K 31/555 20130101; A61K
31/43 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/192 20130101; A61K 2300/00 20130101;
A61K 31/305 20130101; A61K 31/4174 20130101; A61P 43/00 20180101;
A61P 3/02 20180101; A61K 31/216 20130101; A61K 31/19 20130101; A61K
31/44 20130101; A61K 31/43 20130101; C07D 239/34 20130101; A61K
31/5415 20130101; A61K 31/216 20130101; A61K 31/60 20130101; A61K
31/341 20130101; A61K 31/465 20130101; A61K 31/519 20130101; A61K
31/451 20130101; A61K 31/519 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 31/192 20130101; A61K 31/44 20130101; A61P
31/12 20180101; A61K 31/7036 20130101; A61K 31/635 20130101; A61K
45/06 20130101; A61K 9/145 20130101; A61K 31/14 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
504/206 ;
562/575; 544/224; 504/238; 562/473; 504/324; 548/263.2; 504/273;
560/12; 504/302; 544/204; 504/234; 564/441; 504/347 |
International
Class: |
A01N 57/20 20060101
A01N057/20; A01P 13/00 20060101 A01P013/00; C07D 237/14 20060101
C07D237/14; A01N 43/58 20060101 A01N043/58; C07C 65/21 20060101
C07C065/21; A01N 37/10 20060101 A01N037/10; C07D 249/12 20060101
C07D249/12; A01N 43/653 20060101 A01N043/653; C07C 311/53 20060101
C07C311/53; A01N 47/24 20060101 A01N047/24; C07D 251/50 20060101
C07D251/50; A01N 43/68 20060101 A01N043/68; C07C 211/52 20060101
C07C211/52; A01N 33/18 20060101 A01N033/18; C07F 9/30 20060101
C07F009/30 |
Claims
1-193. (canceled)
194. An ionic liquid comprising a cation and an anion, wherein the
ionic liquid is liquid at a temperature at or below about
150.degree. C., and wherein the at least one kind of cation, the at
least one kind of anion, or both are herbicidal actives selected
from the group consisting of carfentrazone, imazapyr, benefin,
acifluorfen,
2-[2-chloro-3-(2,2,2-trifluoroethoxymethyl)-4-methylsulfonylbenzoyl]cyclo-
hexane-1, ethoxysulfuron, flumetsulam, halosulfuron, imazamox,
imazapyr, imazaquin, imazethapyr, metosulam, nicosulfuron,
primisulfuron, prosulfuron, rimsulfuron, thifensulfuron-methyl,
triflusulfuron,
N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-dimethylaminocarbonyl-5--
formylaminobenzenesulfonamide, ametryne, atrazine, bromoxynil,
cyanazine, diuron, hexazinone, metribuzin, pyridate,
terbuthylazine, copyralid, dicamba, diflufenzopyr, fluoroxypyr,
butylate, EPTC, fenoxaprop-P-ethyl, acetochlor, alachlor,
dimethenamid, flufenacet, mefenacet, metolachlor, S-metolachlor,
thenylchlor, fluthiacet-methyl, carfentrazone-ethyl, isoxaflutole,
mesotrione, sulcotrione,
4-(4-trifluoromethyl-2-methylsulfonylbenzoyl)-5-hydroxy-1-methyl-3-methyl-
pyrazole, glyphosate, pendimethalin, trifluralin, asulam,
triaziflam, diflufenican, glufosinate-ammonium, clofencet,
fluoroxpyr, mesosulfuron, diflufenzopyr, or an ionic derivative
thereof.
195. The ionic liquid of claim 1, wherein the ionic liquid is
liquid at a temperature at or below about 125.degree. C.
196. The ionic liquid of claim 1, wherein the ionic liquid is
liquid at a temperature at or below about 75.degree. C.
197. The ionic liquid of claim 1, wherein the ionic liquid is
liquid at a temperature at or below about 50.degree. C.
198. The ionic liquid of claim 1, wherein the ionic liquid is
liquid at a temperature at or below about 25.degree. C.
199. The ionic liquid of claim 1, wherein the composition is liquid
at a temperature from about -30.degree. C. to about 150.degree.
C.
200. The ionic liquid of claim 1, wherein the ionic liquid further
comprises a solvent, preservative, dye, colorant, thickener,
surfactant, a viscosity modifier, or mixture thereof at less than
about 10 wt. % of the total ionic liquid.
201. The ionic liquid of claim 1, wherein the cation is the
herbicidal active.
202. The ionic liquid of claim 1, wherein the anion is the
herbicidal active.
203. The ionic liquid of claim 1, wherein both the cation and anion
are herbicidal actives.
204. The ionic liquid of claim 1, wherein the cation is a
quaternary ammonium ion and the anion is the herbicidal active.
205. The ionic liquid of claim 204, wherein the quaternary ammonium
ion is an aliphatic heteroaryl cation, a dialiphatic dialkyl
ammonium cation, or a tetraaklyl ammonium cation.
206. The ionic liquid of claim 1, wherein the anion is a halide,
sulfate, carbonate, bicarbonate, phosphate, nitrate, nitrite,
acetate, PF.sub.6.sup.-, BF.sub.4.sup.-, triflate, nonaflate,
bis(triflyl)amide, trifluoroacetate, heptafluororobutanoate, or
haloaluminate and the cation is the herbicidal active.
207. A method of controlling plant growth in an area, comprising
administering an effective amount of the ionic liquid of claim 1 to
the area.
208. A method for preparing an ionic liquid, comprising: a.
providing cations and anions, wherein either the cations or anions,
or both cations and anions are herbicidal actives; or providing
cation precursors and anion precursors, wherein either the cation
precursors or anion precursors or both the cation precursors and
anion precursors are herbicidal actives when ionized, wherein the
herbicidal active are selected from the group consisting of
carfentrazone, imazapyr, benefin, acifluorfen,
2-[2-chloro-3-(2,2,2-trifluoroethoxymethyl)-4-methylsulfonylbenzoyl]cyclo-
hexane-1, ethoxysulfuron, flumetsulam, halosulfuron, imazamox,
imazapyr, imazaquin, imazethapyr, metosulam, nicosulfuron,
primisulfuron, prosulfuron, rimsulfuron, thifensulfuron-methyl,
triflusulfuron,
N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-dimethylaminocarbonyl-5--
formylaminobenzenesulfonamide, ametryne, atrazine, bromoxynil,
cyanazine, diuron, hexazinone, metribuzin, pyridate,
terbuthylazine, copyralid, dicamba, diflufenzopyr, fluoroxypyr,
butylate, EPTC, fenoxaprop-P-ethyl, acetochlor, alachlor,
dimethenamid, flufenacet, mefenacet, metolachlor, S-metolachlor,
thenylchlor, fluthiacet-methyl, carfentrazone-ethyl, isoxaflutole,
mesotrione, sulcotrione,
4-(4-trifluoromethyl-2-methylsulfonylbenzoyl)-5-hydroxy-1-methyl-3-methyl-
pyrazole, glyphosate, pendimethalin, trifluralin, asulam,
triaziflam, diflufenican, glufosinate-ammonium, clofencet,
fluoroxpyr, mesosulfuron, diflufenzopyr, or an ionic derivative
thereof; and b. combining the cations and anions or the cation
precursors and anion precursors, thereby producing an ionic liquid
that is liquid at a temperature at or below about 150.degree.
C.
209. The method of claim 14, wherein the ionic liquid is liquid at
a temperature at or below about 125.degree. C.
210. The method of claim 14, wherein the ionic liquid is liquid at
a temperature at or below about 75.degree. C.
211. The method of claim 14, wherein the ionic liquid is liquid at
a temperature at or below about 50.degree. C.
212. The method of claim 14, wherein the ionic liquid is liquid at
a temperature at or below about 25.degree. C.
213. The method of claim 14, wherein the composition is liquid at a
temperature from about -30.degree. C. to about 150.degree. C.
214. The method of claim 208, wherein combining the cations and
anions is accomplished by a metathesis reaction.
215. The method of claim 208, wherein combining the cation
precursor and anion precursor is accomplished by an acid-base
neutralization reaction.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This patent application claims the benefit of priority to
U.S. Provisional Application No. 60/764,850, filed Feb. 2, 2006,
U.S. Provisional Application No. 60/724,604, filed Oct. 7, 2005,
and U.S. Provisional Application No. 60/724,605, filed Oct. 7,
2005, which are each incorporated by reference herein in their
entireties.
FIELD
[0002] The subject matter disclosed herein generally relates to
ionic liquids and to methods of preparing ionic liquid compositions
of active pharmaceutical, biological, nutritional, and energetic
ingredients. Also the subject matter disclosed herein generally
relates to methods of using the compositions described herein to
overcome polymorphism, overcome solubility and delivery problems,
to control release rates, add functionality, enhance efficacy
(synergy), and improve ease of use and manufacture.
BACKGROUND
[0003] Polymorphism is the ability of a substance to exist in two
or more crystalline forms that have a different arrangement and/or
conformation of molecules in a crystalline lattice (see e.g.,
Chawla and Barisal, CRIPS 2004, 5(1):9-12; Bernstein, "Polymorphism
in Molecular Crystals," IUCR Monographs on Crystallography 14,
Oxford Science Publications, 2002, pp. 1-28, 240-256). It has been
estimated that a large number of pharmaceuticals exhibit
polymorphism. For example, 70% of barbiturates, 60% of
sulfonamides, and 23% of steroids are believed to exist in
different polymorphic forms or "polymorphs" (Hateblian et al., J.
Pharm Set 1975, 64:1269-1288).
[0004] In some cases, when crystals of a compound are forming
(e.g., crystallizing from a solution), solvent molecules may become
entrapped or hound within the crystal lattice. The presence of the
entrapped solvent molecules may affect the three-dimensional
crystal lattice that eventually crystallizes. The occurrence of a
compound (target molecule) crystallizing in different
three-dimensional lattices based upon the presence of solvent
molecules has been termed "pseudo-polymorphism." Akin to
polymorphs, such "pseudo-polymorphs," also known as "solvates" (or
"hydrates" when the solvent is water), are crystalline solids
containing either stoichiometric (i.e., whole number ratios of
target molecules to solvent molecules) or non-stoichiometric (i.e.,
non-whole number ratios of target molecules to solvent molecules)
amounts of a solvent incorporated within the crystal structure, in
general, different crystalline forms of molecules (e.g.,
pharmaceutical compounds) can exist in the same or different
hydrated or solvated states.
[0005] The Cambridge Structural Database (Allen, "The Cambridge
Structural Database: a quarter of a million crystal structures and
rising," Acta Ctystallographica, 2002, B58, 380-388) is a database
of over 300,000 organic crystal structures and is a widely used
reference source in crystallography. One survey of the Cambridge
Structural Database shows that pharmaceutical compounds have been
reported to exist as hemi-hydrates (0.5 water molecules) through
decahydrates (10 water molecules). (Morris, "Structural Aspect of
Hydrates and Solvates," Ch. 4 in Polymorphism in Pharmaceutical
Solids, in Brittain, H. G., Ed., Vol. 95 of Drugs and the
Pharmaceutical Sciences, Marcel Dekker, Inc., New York, N.Y., 1999,
125-481.)
[0006] The possibility of polymorphism or pseudo-polymorphism may
exist for any particular compound, but the conditions required to
prepare as yet unknown polymorphs or pseudo-polymorphs are not
easily determined (see e.g., Bernstein, "Crystal Structure
Prediction and Polymorphism," Am Crystallographic Assoc Trans,
2004, 39:14-23). The knowledge that one type of polymorph or
pseudo-polymorph of a crystalline form of a compound exists, or
that a given set of crystallization conditions leads to the
production of one type of polymorph or pseudo-polymorph, does not
typically allow researchers to predict what other types of
polymorph or pseudo-polymorph might exist, or what type of
polymorph or pseudo-polymorph would be produced by other
crystallization conditions (Guillory, "Generation of Polymorphs,
Hydrates, Solvates, and Amorphous Solids," Ch. 5 in Polymorphism in
Pharmaceutical Brittain, H. G., Ed., Vol, 95 of Drugs and the
Pharmaceutical Sciences, Marcel Dekker, Inc., New York, N.Y., 1999,
pp. 183-226).
[0007] The existence of various polymorphs or pseudo-polymorphs can
greatly affect a pharmaceutical's performance since each form can
have different physical and chemical properties. For example, one
particular polymorph pseudo-polymorph may be more bioavailable,
more stable (e.g., longer shelf life), or more easily formulated or
tableted than another polymorph. Similarly, one polymorph
pseudo-polymorph may be more active or less toxic than another.
Some specific examples of the dramatic difference that can exist
between various pharmaceutical polymorphs are described in, e.g.,
Brittain et al., J Pharm Sci 2002, 91:1573-J580 and Morissette et
al., Proc Natl Acad Sci USA 2003, 100:2180-2184.
[0008] The effects of polymorphism and pseudo-polymorphism on
quality and performance of a drug is widely recognized. The exact
solid state polymorph (or pseudo-polymorph) of a compound
determines its physical properties such as dissolution rate,
solubility, bioavailability, crystal habit, mechanical strength,
etc. (Dana et al., Nature Reviews--Drug Discovery, 2004, 3:42-57).
The delivery of an exact dosage in manufacture and the
manufacturing process itself often depend on which of several
possible polymorphs or pseudo-polymorphs are present.
[0009] The variation in properties among different polymorphs (or
pseudo-polymorphs) usually means that one crystalline form is
desired or preferred over other forms. Obtaining a particular form
in can be difficult, however. Typically, researchers have to
experiment with a multitude of variables in crystallization
conditions, such as aqueous solvent mixtures, amount of water,
amount of target compound, relative humidity, temperature of
incubation, incubation time, etc., in a process characterized by
trial and error. Further, the search for salts of crystalline forms
(usually sought after to control dissolution rate and solubility)
can require extensive experimentation. Each salt of a drug or each
different solvent used to crystallize the drag or a salt of the
drug may lead to polymorphs or pseudo-polymorphs that have to be
fully investigated and that have different properties (see e.g.,
Reutzel-Edens et al., "Anhydrates and hydrates of olanzapine:
Crystallization, solid-state characterization, and structural
relationships," Crystal Growth & Design, 2003, 3:897-907).
[0010] Moreover, the inadvertent production of an undesired
polymorph (or pseudo-polymorph), or the spontaneous transformation
from the desired crystalline form to an undesired form, can result
in crystalline forms of a drug that are less effective or even
toxic. Thus, the existence and control of polymorphism and
pseudo-polymorphism can be the biggest challenge to obtaining a
drug product of constant quality.
[0011] Another important issue regarding polymorphism and
pseudo-polymorphism is that there can be considerable regulatory
hurdles for a drug that exists in various crystalline forms. The
FDA's regulatory guidelines emphasize control of crystal form and
the use of appropriate techniques to detect and characterize
different forms of a drug (see Guidance for Industry ANDAs:
Pharmaceutical Solid Polymorphism Chemistry, Manufacturing, and
Controls information, U.S. Department of Health and Human Services,
FDA, 2004). Thus, an applicant seeking FDA approval of a drug must
demonstrate the ability to maintain a constant crystalline form
throughout the life of the product. Such an endeavor is costly and
can be extremely difficult or even impossible.
[0012] Similar challenges can exist when one seeks approval of a
generic product by filing an Abbreviated New Drug Application
(ANDA), in which case the applicant must show equivalence between
the generic drug and an approved drug. Such a showing can be
complicated when various polymorphic and/or pseudo-polymorphic
forms exist for the drug.
[0013] Amorphous forms of drugs are now being studied because they
are higher energy forms that have higher dissolution rates and
solubilities since there is no lattice structure to overcome or to
inhibit salvation (Bernstein, "Polymorphism in Molecular Crystals,"
IUCR Monographs on Crystallography 14, Oxford Science Publications,
2002, pp. 240-256). This increasing attention to amorphous forms
has also shown, however, that the amorphous forms have a tendency
to crystallize spontaneously to a lower energy crystalline form,
usually at inopportune times.
[0014] The phenomenon of polymorphism and pseudo-polymorphism is
not limited to pharmaceuticals as many other (if not all) organic
and inorganic compounds can crystallize into different forms. Thus,
the existence of various forms of a given compound (e.g., a
pesticide, herbicide, nutraceutical, cosmetic, food additive,
explosive, etc.) can result in the same synthetic, analytical,
regulatory, and commercial difficulties that plague the
pharmaceutical industry because of polymorphic and
pseudo-polymorphic drugs. In each of these industries, it is not
currently possible to simply alter the chemical nature of the
active compound in order to tune the chemical (e.g., rate of
dissolution and solubility) or physical (crystal habit, mechanical
strength) properties. Rather, it is often the strategy to search
for polymorphs or pseudo-polymorphs that have the most desirable
"obtainable" properties.
[0015] Another common problem that exists with many pharmaceuticals
is low solubility. Low solubility can make formulating a particular
compound difficult, and generally low solubility translates into
low bioavailability. Much research is conducted on finding ways to
improve a compound's solubility and availability. Typically methods
include complex delivery devices and chemical modifications of the
drug.
[0016] Given that polymorphism and pseudo-polymorphism cannot be
predicted; that the exact crystalline state affects chemical
properties (e.g., dissolution rate, solubility), biological
properties (e.g., bioavailability, pharmacokinetics), mechanical
and physical properties, and manufacturing processes, and that
polymorphs and pseudo-polymorphs can inconveniently interconvert,
what are needed are compositions that are at least effective for
their intended purpose, but can also have controlled and tunable
chemical, biological, and physical properties, are in a form that
is not subject to polymorphism, and for which controlled, tunable
dissolution and solubility are possible. Methods of preparing and
using such compositions are also needed. Further methods of
converting a compound that is difficult to solubilize into a more
soluble form are also desired. The compositions and methods
disclosed herein meet these and other needs including the
introduction of enhanced or new functionality.
SUMMARY
[0017] In accordance with the purposes of the disclosed materials,
compounds, compositions, devices, and methods, as embodied and
broadly described herein, the disclosed subject matter, in one
aspect, relates to compounds and compositions and methods for
preparing and using such compounds and compositions. In a further
aspect, the disclosed subject matter relates to ionic liquid
compositions that can be used for or in biological, pharmaceutical,
nutritional, cosmetic, industrial, and commercial compositions.
Methods for making the disclosed ionic liquid compositions are also
disclosed. Also disclosed are methods of preparing ionic liquid
compositions of active pharmaceutical, biological, nutritional, and
energetic ingredients. Also the disclosed are methods of using the
compositions described herein to overcome polymorphism, overcome
solubility and delivery problems, to control release rates, add
functionality, enhance efficacy (synergy), and improve ease of use
and manufacture.
[0018] Additional advantages will be set forth in part in the
description that follows, and in part will be obvious from the
description, or may be learned by practice of the aspects described
below. The advantages described below will be realized and attained
by means of the elements and combinations particularly pointed out
in the appended claims. It is to be understood that both the
foregoing general description and the following detailed
description are exemplary and explanatory only and are not
restrictive.
BRIEF DESCRIPTION OF THE FIGURES
[0019] The accompanying Figures, which are incorporated in and
constitute a part of this specification, illustrate several aspects
described below.
[0020] FIG. 1 is a graph of absorbance at 258 nanometers (nm) over
time (minutes) for hexadecylpyridinium sulfacetamide
([Hex]sulfacetamide), hexadecylpyridinium chloride ([Hex][Cl]), and
sodium sulfacetamide dissolution.
[0021] FIG. 2 is a graph of absorbance at 258 nm over time for
hexadecylpyridinium sulfacetamide and didecyldimethylammonium (DDA)
sulfacetamide dissolution.
[0022] FIG. 3 is a schematic of a computer model used to identify
ion combinations suitable for the disclosed ionic liquid
combinations.
[0023] FIG. 4A is a graph showing a comparison of lidocaine
hydrochloride and lidocaine docusate at 1 millmolar concentration.
FIG. 4B is a graph showing a comparison of lidocaine hydrochloride
and lidocaine docusate at 100 millimolar concentration.
[0024] FIG. 5 is a graph showing molar conductivity for
[C.sub.4mim]Cl solutions at variable temperature; (.cndot.) 291.0
K; (.cndot.) 295.3 K; (.cndot.) 300.2 K; (.cndot.) 305.0 K in water
and (.cndot.) in DMSO at 295.3 K.
[0025] FIG. 6 is a graph showing the difference in calculated
limiting slope and actually) measured (.cndot.) [C.sub.4mim]Cl in
H.sub.2O at 295.3 K; (.cndot.) [C.sub.4mim]Cl in DMSO at 295.3
K.
DETAILED DESCRIPTION
[0026] The materials, compounds, compositions, articles, and
methods described herein may be understood more readily by
reference to the following detailed description of specific aspects
of the disclosed subject matter and the Examples included
therein.
[0027] Before the present materials, compounds, compositions,
articles, devices, and methods are disclosed and described, it is
to be understood that the aspects described below are not limited
to specific synthetic methods or specific reagents, as such may, of
course, vary. It is also to be understood that the terminology used
herein is for the purpose of describing particular aspects only and
is not intended to be limiting.
[0028] Also, throughout this specification, various publications
are referenced. The disclosures of these publications in their
entireties are hereby incorporated by reference into this
application in order to more fully describe the state of the art to
which the disclosed matter pertains. The references disclosed are
also individually and specifically incorporated by reference herein
for the material contained in them that is discussed in the
sentence in which the reference is relied upon.
General Definitions
[0029] In this specification and in the claims that follow,
reference will be made to a number of terms, which shall be defined
to have the following meanings:
[0030] Throughout the description and claims of this specification
the word "comprise" and other forms of the word, such as
"comprising" and "comprises," means including but not limited to,
and is not intended to exclude, for example, other additives,
components, integers, or steps.
[0031] As used in the description and the appended claims, the
singular forms "a," "an," and "the" include plural referents unless
the context clearly dictates otherwise. Thus, for example,
reference to "a composition" includes mixtures of two or more such
compositions, reference to "an ionic liquid" includes mixtures of
two or more such ionic liquids, reference to "the compound"
includes mixtures of two or more such compounds, and the like.
[0032] "Optional" or "optionally" means that the subsequently
described event or circumstance can or cannot occur, and that the
description includes instances where the event or circumstance
occurs and instances where it does not.
[0033] Ranges can be expressed herein as from "about" one
particular value, and/or to "about" another particular value. When
such a range is expressed, another aspect includes from the one
particular value and/or to the other particular value. Similarly
when values are expressed as approximations, by use of the
antecedent "about," it will be understood that the particular value
forms another aspect. It will be further understood that the
endpoints of each of the ranges are significant both in relation to
the other endpoint, and independently of the other endpoint. It is
also understood that there are a number of values disclosed herein,
and that each value is also herein disclosed as "about" that
particular value in addition to the value itself. For example, if
the value "10" is disclosed, then "about 10" is also disclosed. It
is also understood that when a value is disclosed, then "less than
or equal to" the value, "greater than or equal to the value," and
possible ranges between values are also disclosed, as appropriately
understood by the skilled artisan. For example, if the value "10"
is disclosed, then "less than or equal to 10" as well as "greater
than or equal to 10" is also disclosed. It is also understood that
throughout the application data are provided in a number of
different formats and that this data represent endpoints and
starting points and ranges for any combination of the data points.
For example, if a particular data point "10" and a particular data
point "15" are disclosed, it is understood that greater than,
greater than or equal to, less than, less than or equal to, and
equal to 10 and 15 are considered disclosed as well as between 10
and 15. It is also understood that each unit between two particular
units are also disclosed. For example, if 10 and 15 are disclosed,
then 11, 12, 13, and 14 are also disclosed.
[0034] As used herein, by a "subject" is meant an individual. Thus,
the "subject" can include domesticated animals (e.g., cats, dogs,
etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.),
laboratory animals (e.g., mouse, rabbit, rat, guinea pig, etc.),
and birds. "Subject" can also include a mammal, such as a primate
or a human.
[0035] By "reduce" or other forms of the word, such as "reducing"
or "reduction," is meant lowering of an event or characteristic
(e.g., microorganism growth or survival), it is understood that
this is typically in relation to some standard or expected value,
in other words it is relative, but that it is not always necessary
for the standard or relative value to be referred to. For example,
"reduces bacteria growth" means lowering the amount of bacteria
relative to a standard or a control.
[0036] By "prevent" or other forms of the word, such as
"preventing" or "prevention," is meant to stop a particular event
or characteristic, to stabilize or delay the development or
progression of a particular event or characteristic, or to minimize
the chances that a particular event or characteristic will occur.
Prevent does not require comparison to a control as it is typically
more absolute than, for example, reduce. As used herein, something
could be reduced but not prevented, but something that is reduced
could also be prevented. Likewise, something could be prevented but
not reduced, but something that is prevented could also be reduced.
It is understood that where reduce or prevent are used, unless
specifically indicated otherwise, the use of the other word is also
expressly disclosed.
[0037] By "treat" or other forms of the word, such as "treated" or
"treatment," is meant to administer a composition or to perform a
method in order to reduce, prevent, inhibit, break-down, or
eliminate a particular characteristic or event (e.g., microorganism
growth or survival). The term "control" is used synonymously with
the term "treat."
[0038] By "antimicrobial" is meant the ability to treat or control
(e.g., reduce, prevent, inhibit, break-down, or eliminate)
microorganism growth or survival at any concentration. Similarly,
the terms "antibacterial," "antiviral," and "antifungal"
respectively mean the ability to treat or control (e.g., reduce,
prevent, inhibit, break-down, or eliminate) bacterial, viral, and
funeral growth or survival at any concentration.
[0039] It is understood that throughout this specification the
identifiers "first" and "second" are used solely to aid in
distinguishing the various components and steps of the disclosed
subject matter. The identifiers "first" and "second" are not
intended to imply any particular order, amount, preference, or
importance to the components or steps modified by these terms.
Chemical Definitions
[0040] References in the specification and concluding claims to
parts by weight of a particular element or component in a
composition denotes the weight relationship between the element or
component and any other elements or components in the composition
or article for which a part by weight is expressed. Thus, in a
compound containing 2 parts by weight of component X and 5 parts by
weight component Y, X and Y are present at a weight ratio of 2:5,
and are present in such ratio regardless of whether additional
components are contained in the compound.
[0041] A weight percent (wt. %) of a component, unless specifically
stated to the contrary, is based on the total weight of the
formulation or composition in which the component is included.
[0042] The term "ion," as used herein, refers to any molecule,
portion of a molecule, cluster of molecules, molecular complex,
moiety, or atom that contains a charge (positive, negative, or both
(e.g., zwitterions)) or that can be made to contain a charge.
Methods for producing a charge in a molecule, portion of a
molecule, cluster of molecules, molecular complex, moiety, or atom
are disclosed herein and can be accomplished by methods known in
the art, e.g., protonation, deprotonation, oxidation, reduction,
alkylation, etc.
[0043] The term "anion" is a type of ion and is included within the
meaning of the term "ion." An "anion" is any molecule, portion of a
molecule (e.g., Zwitterion), cluster of molecules, molecular
complex, moiety, or atom that contains a net negative charge or
that can be made to contain a net negative charge. The term "anion
precursor" is used herein to specifically refer to a molecule that
can be converted to an anion via a chemical reaction (e.g.,
deprotonation).
[0044] The term "cation" is a type of ion and is included within
the meaning of the term "ion." A "cation" is any molecule, portion
of a molecule (e.g., Zwitterion), cluster of molecules, molecular
complex, moiety, or atom, that contains a net positive charge or
that can be made to contain a net positive charge. The term "cation
precursor" is used herein to specifically refer to a molecule that
can be converted to a cation via a chemical reaction (e.g.,
protonation alkylation).
[0045] As used herein, the term "substituted" is contemplated to
include all permissible substituents of organic compounds. In a
broad aspect, the permissible substituents include acyclic and
cyclic, branched and unbranched, carbocyclic and heterocyclic, and
aromatic and nonaromatic substituents of organic compounds.
Illustrative substituents include, for example, those described
below. The permissible substituents can be one or more and the same
or different for appropriate organic compounds. For purposes of
this disclosure, the heteroatoms, such as nitrogen, can have
hydrogen substituents and/or any permissible substituents of
organic compounds described herein which satisfy the valencies of
the heteroatoms. This disclosure is not intended to be limited in
any manner by the permissible substituents of organic compounds.
Also, the terms "substitution" or "substituted with" include the
implicit proviso that such substitution is in accordance with
permitted valence of the substituted atom and the substituent, and
that the substitution results in a stable compound, e.g., a
compound that does not spontaneously undergo transformation such as
by rearrangement, cyclization, elimination, etc.
[0046] "A.sup.1," "A.sup.2," "A.sup.3," and "A.sup.4" are used
herein as generic symbols to represent various specific
substituents. These symbols can be any substituent, not limited to
those disclosed herein, and when they are defined to be certain
substituents in one instance, they can, in another instance, be
defined as some other substituents.
[0047] The term "aliphatic" as used herein refers to a non-aromatic
hydrocarbon group and includes branched and unbranched, alkyl,
alkenyl, alkynyl groups.
[0048] The term "alkyl" as used herein is a branched or unbranched
saturated hydrocarbon group of 1 to 24 carbon atoms, such as
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl,
pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl,
hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can
also be substituted or unsubstituted. The alkyl group can be
substituted with one or more groups including, but not limited to,
alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl,
heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide,
hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone,
sulfoxide, or thiol, as described below.
[0049] Throughout the specification "alkyl" is generally used to
refer to both unsubstituted alkyl groups and substituted alkyl
groups; however, substituted alkyl groups are also specifically
referred to herein by identifying the specific substituent(s) on
the alkyl group. For example, the term "halogenated alkyl"
specifically refers to an alkyl group that is substituted with one
or more halide, e.g., fluorine, chlorine, bromine, or iodine. The
term "alkoxyalkyl" specifically refers to an alkyl group that is
substituted with one or more alkoxy groups, as described below. The
term "alkylamino" specifically refers to an alkyl group that is
substituted with one or more amino groups, as described below, and
the like. When "alkyl" is used in one instance and a specific term
such as "alkylalcohol." is used in another, it is not meant to
imply that the term "alkyl" does not also refer to specific terms
such as "alkylalcohol." and the like.
[0050] This practice is also used for other groups described
herein. That is, while a term such as "cycloalkyl" refers to both
unsubstituted and substituted cycloalkyl moieties, the substituted
moieties can, in addition, be specifically identified herein; for
example, a particular substituted cycloalkyl can be referred to as,
e.g., an "alkylcycloalkyl." a substituted alkoxy can be
specifically referred to as, e.g., a "halogenated alkoxy," a
particular substituted alkenyl can be, e.g., an "alkenylalcohol,"
and the like. Again, the practice of using a general term, such as
"cycloalkyl," and a specific term, such as "alkylcycloalkyl," is
not meant to imply that the general term does not also include the
specific term.
[0051] The term "alkoxy" as used herein is an alkyl group bound
through a single, terminal ether linkage; that is, an "alkoxy"
group can be defined as --OA.sup.1 where A.sup.1 is alkyl as
defined above.
[0052] The term "alkenyl" as used herein is a hydrocarbon group of
from 2 to 24 carbon atoms with a structural formula containing at
least one carbon-carbon double bond. Asymmetric structures such as
(A.sup.1A.sup.2)C.dbd.C(A.sup.3A.sup.4) are intended to include
both the E and Z isomers. This may be presumed in structural
formulae herein wherein an asymmetric alkene is present, or it may
be explicitly indicated by the bond symbol C.dbd.C. The alkenyl
group can be substituted with one or more groups including, but not
limited to, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl,
aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,
halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl,
sulfone, sulfoxide, or thiol, as described below.
[0053] The term "alkynyl" as used herein is a hydrocarbon group of
2 to 24 carbon atoms with a structural formula containing at least
one carbon-carbon triple bond. The alkynyl group can be substituted
with one or more groups including, but not limited to, alkyl,
halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl,
aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy,
ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or
thiol, as described below.
[0054] The term "aryl" as used herein is a group that contains any
carbon-based aromatic group including, but not limited to, benzene,
naphthalene, phenyl, biphenyl, phenoxybenzene, and the like. The
term "aryl" also includes "heteroaryl," which is defined as a group
that contains an aromatic group that has at least one heteroatom
incorporated within the ring of the aromatic group. Examples of
heteroatoms include, but are not limited to, nitrogen, oxygen,
sulfur, and phosphorus. Likewise, the term "non-heteroaryl," which
is also included in the term "aryl," defines a group that contains
an aromatic group that does not contain a heteroatom. The aryl
group can be substituted or unsubstituted. The aryl group can be
substituted with one or more groups including, but not limited to,
alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl,
heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide,
hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone,
sulfoxide, or thiol as described herein. The term "biaryl" is a
specific type of aryl group and is included in the definition of
aryl. Biaryl refers to two aryl groups that are bound together via
a fused ring structure, as in naphthalene, or are attached via one
or more carbon-carbon bonds, as in biphenyl.
[0055] The term "cycloalkyl" as used herein is a non-aromatic
carbon-based ring composed of at least three carbon atoms. Examples
of cycloalkyl groups include, but are not limited to, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, etc. The term
"heterocycloalkyl" is a cycloalkyl group as defined above where at
least one of the carbon atoms of the ring is substituted with a
heteroatom such as, but not limited to, nitrogen, oxygen, sulfur,
or phosphorus. The cycloalkyl group and heterocycloalkyl group can
be substituted or unsubstituted. The cycloalkyl group and
heterocycloalkyl group can be substituted with one or more groups
including, but not limited to, alkyl, alkoxy, alkenyl, aryl,
heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide,
hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone,
sulfoxide, or thiol as described herein.
[0056] The term "cycloalkenyl" as used herein is a non-aromatic
carbon-based ring composed of at least three carbon atoms and
containing at least one double bound, i.e., C.dbd.C. Examples of
cycloalkenyl groups include, but are not limited to, cyclopropenyl,
cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,
cyclohexadienyl, and the like. The term "heterocycloalkenyl" is a
type of cycloalkenyl group as defined above, and is included within
the meaning of the term "cycloalkenyl," where at least one of the
carbon atoms of the ring is substituted with a heteroatom such as,
but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The
cycloalkenyl group and heterocycloalkenyl group can be substituted
or unsubstituted. The cycloalkenyl group and heterocycloalkenyl
group can be substituted with one or more groups including, but not
limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl,
aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy,
ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or
thiol as described herein.
[0057] The term "cyclic group" is used herein to refer to either
aryl groups, non-aryl groups (i.e., cycloalkyl, heterocycloalkyl,
cycloalkenyl, and heterocycloalkenyl groups), or both. Cyclic
groups have one or more ring systems that can be substituted or
unsubstituted. A cyclic group can contain one or more aryl groups,
one or more non-aryl groups, or one or more aryl groups and one or
more non-aryl groups.
[0058] The term "aldehyde" as used herein is represented by the
formula C(O)H. Throughout this specification "C(O)" is a short hand
notation for C.dbd.O.
[0059] The terms "amine" or "amino" as used herein are represented
by the formula NA.sup.1A.sup.2A.sup.3, where A.sup.1, A.sup.2, and
A.sup.3 can be, independently, hydrogen, an alkyl, halogenated
alkyl, alkenyl, alkenyl, aryl, heteroaryl, cycloalkyl,
cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group
described above.
[0060] The term "carboxylic acid" as used herein is represented by
the formula C(O)OH. A "carboxylate" as used herein is represented
by the formula --C(O)O.sup.-.
[0061] The term "ester" as used herein is represented by the
formula --OC(O)A.sup.1 or --C(O)OA.sup.1, where A.sup.1 can be an
alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl
group described above.
[0062] The term "ether" as used herein is represented by the
formula A.sup.1OA.sup.2, where A.sup.1 and A.sup.2 can be,
independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or
heterocycloalkenyl group described above.
[0063] The term "ketone" as used herein is represented by the
formula A.sup.1C(O)A.sup.2, where A.sup.1 and A.sup.2 can be,
independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or
heterocycloalkenyl group described above.
[0064] The term "halide" as used herein refers to the halogens
fluorine, chlorine, bromine, and iodine.
[0065] The term "hydroxyl" as used herein is represented by the
formula --OH.
[0066] The term "nitro" as used herein is represented by the
formula --NO.sub.2.
[0067] The term "silyl" as used herein is represented by the
formula --SiA.sup.1A.sup.2A.sup.3, where A.sup.1, A.sup.2, and
A.sup.3 can be, independently, hydrogen, alkyl, halogenated alkyl,
alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,
cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group
described above.
[0068] The term "sulfo-oxo" as used herein is represented by the
formulas --S(O)A.sup.1, --S(O).sub.2A.sup.1, --OS(O).sub.2A.sup.1,
or --OS(O).sub.2OA.sup.1, where A.sup.1 can be hydrogen, an alkyl,
halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl,
cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group
described above. Throughout this specification "S(O)" is a short
hand notation for S.dbd.O.
[0069] The term "sulfonyl" is used herein to refer to the sulfo-oxo
group represented by the formula --S(O).sub.2A.sup.1, where A.sup.1
can be hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl,
aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or
heterocycloalkenyl group described above.
[0070] The term "sulfonylamino" or "sulfonamide" as used herein is
represented by the formula --S(O).sub.2NH--.
[0071] The term "sulfone" as used herein is represented by the
formula A.sup.1S(O).sub.2A.sup.2, where A.sup.1 and A.sup.2 can be,
independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or
heterocycloalkenyl group described above.
[0072] The term "sulfoxide" as used herein is represented by the
formula A.sup.1S(O)A.sup.2 where A.sup.1 and A.sup.2 can be,
independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl,
heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or
heterocycloalkenyl group described above.
[0073] The term "thiol" as used herein is represented by the
formula --SH.
[0074] "R.sup.1," "R.sup.2," "R.sup.3," "R.sup.n," etc., where n is
some integer, as used herein can, independently, possess one or
more of the groups listed above. For example, if R.sup.1 is a
straight chain alkyl group, one of the hydrogen atoms of the alkyl
group can optionally be substituted with a hydroxyl group, an
alkoxy group, an amine group, an alkyl group, a halide, and the
like. Depending upon the groups that are selected, a first group
can be incorporated within second group or, alternatively, the
first group can be pendant (i.e., attached) to the second group.
For example, with the phrase "an alkyl group comprising an amino
group," the amino group can be incorporated within the backbone of
the alkyl group. Alternatively, the amino group can be attached to
the backbone of the alkyl group. The nature of the group(s) that is
(are) selected will determine if the first group is embedded or
attached to the second group.
[0075] The term "bioactive property" is any local or systemic
biological, physiological, or therapeutic effect in a biological
system. For example, the bioactive property can be the control of
infection or inflammation, enhancement or suppression of growth,
action as an analgesic, anti-viral, pesticidal, herbicidal, or
nutrientional action, etc. Many examples of bioactive properties
are disclosed herein.
[0076] The term "energetic" is used to described a compound having
a heat of combustion of greater than about 500 kcal/mol (e.g.,
about 750, 1000, 1500 kcal/mol or more).
[0077] Unless stated to the contrary, a formula with chemical bonds
shown only as solid lines and not as wedges or dashed lines
contemplates each possible isomer, e.g., each enantiomer,
diastereomer, and meso compound, and a mixture of isomers, such as
a racemic or scalemic mixture.
[0078] Reference will now be made in detail to specific aspects of
the disclosed materials, compounds, compositions, articles, and
methods, examples of which are illustrated in the accompanying
Examples.
Materials and Compositions
[0079] Certain materials, compounds, compositions, and components
disclosed herein can be obtained commercially or readily
synthesized using techniques generally known to those of skill in
the art. For example, the starting materials and reagents used in
preparing the disclosed compounds and compositions are either
available from commercial suppliers such as Aldrich Chemical Co.,
(Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher
Scientific (Pittsburgh, Pa.), Sigma (St. Louis, Mo.), Pfizer (New
York, N.Y.), GlaxoSmithKline (Raleigh, N.C.), Merck (Whitehouse
Station, N.J.), Johnson & Johnson (New Brunswick, N.J.),
Aventis (Bridgewater, N.J.), AstraZeneca (Wilmington, Del.),
Novartis (Basel, Switzerland), Wyeth (Madison, N.J.),
Bristol-Myers-Squibb (New York, N.Y.), Roche (Basel, Switzerland),
Lilly (Indianapolis, Ind.), Abbott (Abbott Park, Ill.), Schering
Plough (Kenilworth, N.J.), or Boehringer Ingelheim (Ingelheim,
Germany), or are prepared by methods known to those skilled in the
art following procedures set forth in references such as Fieser and
Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley
and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5
and Supplemental's (Elsevier Science Publishers, 1989); Organic
Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March's
Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and
Larock's Comprehensive Organic Transformations (VCH Publishers
Inc., 1989). Other materials, such as the active pharmaceutical
ingredients, pesticides, herbicides, and other biological agents
disclosed herein can be obtained from commercial sources.
[0080] In one aspect, disclosed herein are ionic liquid
compositions. The term "ionic liquid" has many definitions in the
art, but is used herein to refer to salts (i.e., compositions
comprising cations and anions) that are liquid at a temperature of
at or below about 150.degree. C. That is, at one or more
temperature ranges or points at or below about 150.degree. C. the
disclosed ionic liquid compositions are liquid; although, it is
understood that they can be solids at other temperature ranges or
points. Since the disclosed ionic liquid compositions are liquid,
and thus not crystalline solids, at a given temperature, the
disclosed compositions do not stiffer from the problems of
polymorphism associated with crystalline solids.
[0081] The use of the term "liquid" to describe the disclosed ionic
liquid compositions is meant to describe a generally amorphous,
non-crystalline, or semi-crystalline state. For example, while some
structured association and packing of cations and anions can occur
at the atomic level, the disclosed ionic liquid compositions have
minor amounts of such ordered structures and are therefore not
crystalline solids. The compositions disclosed herein can be fluid
and free-flowing liquids or amorphous solids such as glasses or
waxes at a temperature at or below about 150.degree. C. In
particular examples disclosed herein, the disclosed ionic liquid
compositions are liquid at the body temperature of a subject.
[0082] Further, the disclosed ionic liquid compositions are
materials composed of at least two different ions; each of which
can independently and simultaneously introduce a specific
characteristic to the composition not easily obtainable with
traditional dissolution and formulation techniques. Thus, by
providing different ions and ion combinations, one can change the
characteristics or properties of the disclosed ionic liquid
compositions in a way not seen by simply preparing various
crystalline salt forms. Examples of characteristics that can be
controlled in the disclosed compositions include, but are not
limited to, melting, solubility control, and rate of dissolution.
It is this multi-nature/functionality of the disclosed ionic liquid
compositions which allows one to fine-tune or design in very
specific desired material properties.
[0083] It is further understood that the disclosed ionic liquid
compositions can include solvent molecules (e.g., water); however,
these solvent molecules should not be present in excess in the
sense that the disclosed ionic liquid compositions are dissolved in
the solvent, forming a solution. That is, the disclosed ionic
liquid compositions contain no or minimal amounts of solvent
molecules that are free and not bound or associated with the ions
present in the ionic liquid composition. Thus, the disclosed ionic
liquid compositions can be liquid hydrates or solvates, but not
solutions.
[0084] Ionic liquids have been of general interest because they are
environmentally-friendly alternatives to organic solvents for
various chemical processes, e.g., liquid/liquid extractions,
catalysis, separations, and electrochemistry. Ionic liquids have
also become popular alternative media for chemical synthesis
because of their low volatility and low toxicity. See e.g.,
Wasserscheid and Keim, Angew Chem Int Ed Engl., 2000, 39:3772; and
Wasserscheid, "Ionic Liquids in Synthesis," 1.sup.st Ed.,
Wiley-VCH, 2002. Further, ionic liquids can reduce costs, disposal
requirements, and hazards associated with volatile organic
compounds. Other exemplary properties of ionic liquids are high
ionic conductivity, non-volatility, non-flammability, high thermal
stability, wide temperature for liquid phase, highly solvability,
and non-coordinating. For a review of ionic liquids see, for
example, Welton, Chem Rev. 1999, 99:2071-2083; and Carlin et al.,
Advances in Nonaqueous Chemistry, Mamantov et al. Eds., VCH
Publishing, New York, 1994.
[0085] The specific physical properties (e.g., melting point,
viscosity, density, water solubility, etc.) of ionic liquids are
determined by the choice of cation and anion, as is disclosed more
fully herein. As an example, the melting point for an ionic liquid
can be changed by making structural modifications to the ions or by
combining different ions. Similarly, the particular chemical
properties (e.g., bioactivity, toxicity, pharmacokinetics, etc.),
can be selected by changing the constituent ions of the ionic
liquid.
[0086] The ionic liquid compositions disclosed herein are comprised
of at least one kind of anion and at least one kind of cation. The
at least one kind of cation, the at least one kind of anion, or
both can be a pharmaceutical active, a pesticidal active, a
herbicidal active, a food additive, a nutraceutical, or the like,
including any combination thereof, as is disclosed herein. It is
contemplated that the disclosed ionic liquid compositions can
comprise one kind of cation with more than one kind of anion (e.g.,
2, 3, 4, 5, 6, 7, 9, 10, or more different kinds of anions).
Likewise, it is contemplated that the disclosed ionic liquid
compositions can comprise one kind of anion with more than one kind
of cation (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more different
kinds of cations). Further, the disclosed ionic liquids can
comprise more than one kind of anion (e.g., 2, 3, 4, 5, 6, 7, 8, 9,
10, or more different kinds of anions) with more than one kind of
cation (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10 or more different kinds of
cations). Specific examples include, but are not limited to, one
kind of cation with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of
anions, 2 kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or
more kinds of anions, 3 kinds of cations with 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, or more kinds of anions, 4 kinds of cations with 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, or more kinds of anions, 5 kinds of cations
with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of anions, 6
kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds
of anions, 2 kinds of cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
or more kinds of anions, 8 kinds of cations with 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, or more kinds of anions, 9 kinds of cations with 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, or more kinds of anions, 10 kinds of
cations with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of
anions, or more than 10 kinds of cations with 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, or more kinds of anions.
[0087] Other specific examples include, but are not limited to, one
kind of anion with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of
cations, 2 kinds of anions with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or
more kinds of cations, 3 kinds of anions with 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, or more kinds of cations, 4 kinds of anions with 1, 2, 3,
4, 5, 6, 7, 8, 9, 10, or more kinds of cations, 5 kinds of anions
with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of cations, 6
kinds of anions with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds
of cations, 7 kinds of anions with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
or more kinds of cations, 8 kinds of anions with 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, or more kinds of cations, 9 kinds of anions with 1, 2,
3, 4, 5, 6, 7, 8, 9, 10, or more kinds of cations, 10 kinds of
anions with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more kinds of
cations, or more than 10 kinds of anions with 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, or more kinds of cations.
[0088] In addition to the cations and anions, the ionic liquid
compositions disclosed herein can also contain nonionic species,
such as solvents, preservatives, dyes, colorants, thickeners,
surfactants, viscosity modifiers, mixtures and combinations thereof
and the like. However, the amount of such nonionic species is
typically low (e.g., less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, or
1 wt. % based on the total weight of the composition). In some
examples described herein, the disclosed ionic liquid compositions
are neat; that is, the only materials present in the disclosed
ionic liquids are the cations and anions that make up the ionic
liquid compositions. It is understood, however, that with neat
compositions, some additional materials or impurities can sometimes
be present, albeit at low to trace amounts (e.g., less than about
10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 wt. % based on the total weight of
the composition).
[0089] The disclosed ionic liquid compositions are liquid at some
temperature range or point at or below about 150.degree. C. For
example, the disclosed ionic liquids can be a liquid at or below
about 150, 149, 148, 147, 146, 145, 144, 143, 142, 141, 140, 139,
138, 137, 136, 135, 134, 133, 132, 131, 130, 129, 128, 127, 126,
125, 124, 123, 122, 121, 120, 119, 118, 117, 116, 115, 114, 113,
112, 111, 110, 109, 108, 107, 106, 105, 104, 103, 102, 101, 100,
99, 98, 97, 96, 95, 94, 93, 92, 91, 90, 89, 88, 87, 86, 85, 84, 83,
82, 81, 80, 79, 78, 77, 76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66,
65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49,
48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32,
31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15,
14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0, -1, -2, -3, -4,
-5, -6, -7, -9, -10, -11, -12, -13, -14, -15, -16, -17, -18, -19,
-20, -21, -22, -23, -24, -25, -26, -27, -28, -29, or -30.degree.
C., where any of the stated values can form an upper or lower
endpoint when appropriate. In further examples, the disclosed ionic
liquids can be liquid at any point from about -30.degree. C. to
about 150.degree. C., from about -20.degree. C. to about
140.degree. C., -10.degree. C. to about 130.degree. C., from about
0.degree. C. to about 120.degree. C., from about 10.degree. C. to
about 110.degree. C., from about 20.degree. C. to about 100.degree.
C., from about 30.degree. C. to about 90.degree. C., from about
40.degree. C. to about 80.degree. C., from about 50.degree. C. to
about 70.degree. C., from about -30.degree. C. to about 50.degree.
C., from about -30.degree. C. to about 90.degree. C., from about
30.degree. C. to about 110.degree. C., from about -30.degree. C. to
about 130.degree. C., from about -30.degree. C. to about
150.degree. C., from about 30.degree. C. to about 90.degree. C.,
from about 30.degree. C. to about 110.degree. C., from about
30.degree. C. to about 130.degree. C., from about 30.degree. C. to
about 150.degree. C., from about 0.degree. C. to about 100.degree.
C., from about 0.degree. C. to about 70.degree. C., from about 0''
to about 50.degree. C., and the like.
[0090] Further, in some examples the disclosed ionic liquid
compositions can be liquid over a wide range of temperatures, not
just a narrow range of, say, 1-2 degrees. For example, the
disclosed ionic liquid compositions can be liquids over a range of
at least about 4, 5, 6, 7, 8, 9, 10, or more degrees. In other
example, the disclosed ionic liquid compositions can be liquid over
at least about a 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more
degree temperature range. Such temperature ranges can begin and/or
end at any of the temperature points disclosed in the preceding
paragraph.
[0091] In many examples disclosed herein the disclosed ionic liquid
compositions are liquid at the temperature at which they will be
used or processed. For example, many of the disclosed ionic liquid
compositions can be used for therapeutic or nutritional purposes in
a subject. In this case, the disclosed ionic liquid compositions
can be liquid at the subject's body temperature (e.g., about
37.degree. C. for a human). Other examples include compositions
that can be used as herbicides or pesticides, which are liquid at
the temperature of their use (e.g., ambient temperature). In still
other examples, the disclosed compositions can be liquid at the
temperature at which they are formulated or processed.
[0092] It is understood, however, that the disclosed ionic liquid
compositions can, though need not, be solubilized, and solutions of
the disclosed ionic liquids are contemplated herein. Further, the
disclosed ionic liquid compositions can be formulated in an
extended or controlled release vehicle, for example, by
encapsulating the ionic liquids in microspheres or microcapsules
using methods known in the art. Still further, the disclosed ionic
liquid compositions can themselves be solvents for other solutes.
For example, the disclosed ionic liquids can be used to dissolve a
particular nonionic or ionic pharmaceutical active. These and other
formulations of the disclosed ionic liquids are disclosed elsewhere
herein.
[0093] In some examples, the disclosed ionic liquids are not
solutions where ions are dissolved in a solute. In other examples,
the disclosed ionic liquid compositions do not contain ionic
exchange resins. In still other examples, the disclosed ionic
liquids are substantially free of water. By substantially free is
meant that water is present at less than about 10, 9, 8, 7, 6, 5,
4, 3, 2, 1, 0.5, 0.25, or 0.1 wt. %, based on the total weight of
the composition.
[0094] The disclosed ionic liquid compositions can be prepared by
methods described herein. Generally, the particular cation(s) and
anion(s) used to prepare the disclosed ionic liquids are selected
as described herein. Then, with the particular cation(s) and
anion(s) in hand, they can be combined, resulting in ionic liquid
compositions as disclosed herein. Additionally, the method for the
preparation of the disclosed ionic liquid compositions can include
the reaction in which two neutral species: an anion precursor
(e.g., in the form of an inorganic acid, carboxylic organic acid,
non-carboxylic acid, or Zwitterion species) and a cation precursor
(e.g., inorganic base, organic base, Zwitterion species) are
combined resulting in ionic liquid compositions as disclosed
herein.
[0095] Providing ions used to prepare the disclosed ionic liquids
depends, in one aspect, on the desired properties of the resulting
ionic liquid composition. As described herein, the disclosed ionic
liquid compositions can have multiple desired properties, which, at
least in part, come from the properties of the cation(s) and/or
anion(s) used to prepare the ionic liquid. Thus, to prepare the
disclosed ionic liquids, one or more kinds of cations with a
desired property(ies) are provided. One or more kinds of anions
with a desired property(ies) that is similar or different to that
of the cation(s) can likewise be provided. Of course, providing a
desired anion(s) and cation(s) can be done in any order, depending
on the preference and aims of the practitioner. For example, a
particular cation(s) can be provided and then a particular anion(s)
can be provided. Alternatively, a particular anion(s) can be
provided and then a particular cation(s) can be provided. Further,
the cation(s) and anion(s) can be provided simultaneously.
[0096] As noted, providing a suitable ion can be based on selecting
an ion that possesses a property that is desired (e.g., the ion has
a property that is desired to be possessed by the resulting ionic
liquid). Examples of properties that could be desired in a suitable
cation and/or anion (and thus the ionic liquid made therefrom)
include, but are not limited to, biological, therapeutic,
prophylactic, nutritional, pesticidal, and/or herbicidal activity.
Inertness, taste, viscosity modulation, solubility modulation,
stability, and toxicity are other properties of a given ion that
could be desired and considered. While more specific properties are
disclosed elsewhere herein, the disclosed methods and compositions
are not limited to any particular combination of properties, as
such will depend on the preferences and goals of the
practitioner.
[0097] Typically, the desired properties of the cation(s) and
anion(s) will be different or complimentary to one another. In this
way, the resulting ionic liquid can possess multiple desired
properties: those properties imparted by the cation(s) and those
imparted by the anion(s). In other words, some or all of the ions
present in the disclosed ionic liquids can independently and
simultaneously introduce a specific functionality or property to
the disclosed ionic liquid compositions. It is this multiple
functionality characteristic that can allow one to fine-tune or
design very specific physical, chemical, and bioactive properties
in the disclosed ionic liquid compositions. Additional
functionality can be obtained by using the disclosed ionic liquid
compositions as solvents to dissolve a solute(s) with another
desired property, thus resulting in a solution where the ions of
the ionic liquid as well as the solute contribute desired
properties to the composition. General and specific examples of
various combinations of ions and their associated properties are
disclosed herein.
[0098] In some particular examples, one or more ions in the
disclosed ionic liquid composition (e.g., the anions, cations, or
both) can be a pharmaceutical active, e.g., an existing drug that
is ionic or that can be made ionic. Many drugs exist naturally or
at physiological conditions as an ion, or they can be converted to
ions via simple chemical transformations (e.g., alkylation,
protonation, deprotonation, etc.). As such, these drugs can be used
to prepare an ionic liquid composition as disclosed herein. Such
drugs can possess any therapeutic or prophylactic activity, many of
which are described herein. Combining such drugs with other ions to
prepare an ionic liquid, as is disclosed herein, can result in the
modification and/or enhancement of the drug's properties. For
example, a first drug ion with a given property can be combined
with an oppositely charged second ion with another property to
effect the controlled release, controlled delivery, biological
impact, taste, physical properties (stability, solubility,
toxicity, melting point, etc.), or to overcome polymorphism in the
first drug ion. In this way, new drug compositions can be created
by forming ionic liquids with functionality crafted into the
combination of the ions, as disclosed herein.
[0099] As another example, the first drug ion may be combined with
a second drug ion that has properties complimentary to the first.
Examples of this can include, but are not limited to, an ion having
anesthetic properties being combined with an ion having
antibacterial properties, an ion having anesthetic properties being
combined with an ion having coagulation properties, or an ion
having coagulation properties being combined with an ion having
antibacterial properties. Ionic liquids resulting from such
combinations could find uses in wound repair, for example. Still
other examples of desirable combination include ions having
therapeutic or prophylactic efficacy being combined with ions
having taste enhancement properties (i.e., taste modifiers). Ionic
liquids resulting from this combination can be useful in enhancing
the taste and palatability of medicines. Still further examples can
include two differently charged ions each with similar uses but
with different mechanisms of action. Specific examples of such
combinations can include, but are not limited to, combinations of
ions with antineoplastic properties or antiviral properties. Ionic
liquids prepared from such ion combinations can be useful as drug
"cocktails," where two or more bioactive agents are present in a
single ionic liquid combination.
[0100] According to the methods and compositions disclosed herein,
ion identification and combination, as disclosed herein, can
involve any ion, not just ionic drugs, as long as the combination
results in an ionic liquid. For example, ions that have pesticidal
properties can be combined with oppositely charged ions having
pesticidal, herbicidal, antimicrobial properties, and the like. In
other examples, ions with antibacterial properties can be combined
with oppositely charges ions that have preservative properties,
taste modifiers, etc. In still other examples, an ion with one
therapeutic or prophylactic property can be combined with another
therapeutic or prophylactic ion. As should be appreciated, the
various combinations of ions according to the disclosed methods are
numerous, and depend only on the desired combination of properties
and whether the resulting ion combination is an ionic liquid as
defined herein.
[0101] Specific examples of properties that can be exhibited by the
disclosed compositions include antibacterial, FDA approved dyes,
anti-acne, antibiotic, UV blocker, wetting agents, preservative,
emollient, anti-inflammatory, and vitamin.
[0102] Ions
[0103] The disclosed ionic liquids contain at least one kind of
cation and at least one kind of anion. Examples of suitable cations
and anions are disclosed herein. It should be understood that When
a particular compound is disclosed as being a cation, for example,
it can also, in other circumstances, be an anion and vice versa.
Many compounds are known to exist as cations in some environments
and anions in other environments. Further, many compounds are known
to be convertible to cations and anions through various chemical
transformations. Examples of such compounds are disclosed
herein.
[0104] The materials, compounds, compositions, and components that
can be used for, can be used in conjunction with, can be used in
preparation for, or are products of the disclosed methods and
compositions are disclosed herein. It is understood that when
combinations, subsets, interactions, groups, etc. of these
materials are disclosed that while specific reference of each
various individual and collective combinations and permutation of
these compounds may not be explicitly disclosed, each is
specifically contemplated and described herein. For example, if an
ionic liquid composition is disclosed and a number of modifications
that can be made to a number of components of the ionic liquid
composition are discussed, each and every combination and
permutation that are possible are specifically contemplated unless
specifically indicated to the contrary. Thus, if a class of cations
A, B, and C are disclosed as well as a class of anions D, E, and F
and an example of a ionic liquid A-D is disclosed, then even if
each is not individually recited, each is individually and
collectively contemplated. Thus, in this example, each of the ionic
liquids A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are specifically
contemplated and should be considered disclosed from disclosure of
A, B, and C; D, E, and F; and the example ionic liquid A-D.
Likewise, any subset or combination of these is also specifically
contemplated and disclosed. Thus, for example, the sub-group of
A-E, B-F, and C-E are specifically contemplated and should be
considered disclosed from disclosure of A, B, and C; D, E, and F;
and the example combination A-D. This concept applies to all
aspects of this disclosure including, but not limited to, steps in
methods of making and using the disclosed compositions. Thus, if
there are a variety of additional steps that can be performed it is
understood that each of these additional steps can be performed
with any specific aspect or combination of aspects of the disclosed
methods, and that each such combination is specifically
contemplated and should be considered disclosed.
[0105] Cations
[0106] Particular examples of cationic compounds that can be
present in the disclosed ionic liquid compositions are compounds
that contain nitrogen atoms. Nitrogen atoms can exist or can be
converted to positively-charged quaternary ammonium species, for
example, through alkylation or protonation of the nitrogen atom.
Thus compounds that possess a quaternary nitrogen atom (known as
quaternary ammonium compounds (QACs)) are typically cations.
According to the methods and compositions disclosed herein, any
compound that contains a quaternary nitrogen atom or a nitrogen
atom that can be convened into a quaternary nitrogen atom can be a
suitable cation for the disclosed ionic liquid compositions.
[0107] QACs can have numerous biological properties that one may
desire to be present in the disclosed ionic liquid compositions.
For example, many QACs are known to have antibacterial properties.
The antibacterial properties of QACs were first observed toward the
end of the 19.sup.th century among the carbonium dyestuffs, such as
auramin, methyl violet, and malachite green. These types of
compounds are effective chiefly against the Gram-positive
organisms. Jacobs and Heidelberger first discovered QACs
antibacterial effect in 1915 studying the antibacterial activity of
substituted hexamethylene-tetrammonium salts (Jacobs and
Heidelberger, Proc Nat Acad Sci USA, 1915, 1:226; Jacobs and
Heidelberger, J Biol Chem, 1915, 20:659; Jacobs and Heidelberger, J
Exptl Med, 1916, 23:569).
[0108] Browning et al. found great and somewhat less selective
bactericidal powers among quaternary derivatives of pyridine,
quinoline, and phenazine (Browning et al., Proc Roy Soc London,
1922, 93B:329; Browning et al., Proc Roy Soc London, 1926,
100B:293). Hartman and Magi observed antibacterial activity in QACs
of acylated alkylene diamines (Hartman and Kagi, Z Angew Chem,
1928, 4:127).
[0109] In 1935, Domagk synthesized long-chain QACs, including
benzalkonium chloride, and characterized their antibacterial
activities (Domagk, Deut Med Wochenschr, 1935, 61:829). He showed
that these salts are effective against a wide variety of bacterial
strains. This study of the use of QACs as germicides was greatly
stimulated.
[0110] Many scientists have focused their attention on water
soluble QACs because they exhibit a range of properties: they are
surfactants, they destroy bacteria and fungi, they serve as a
catalyst in phase-transfer catalysis, and they show
anti-electrostatic and anticorrosive properties. They exert
antibacterial action against both Gram-positive and Gram-negative
bacterial as well as against some pathogen species of fungi and
protozoa. These multifunctional salts have also been used in wood
preservation, their application promoted in the papers of Oertel
and Butcher et (Oertel, Hoiztechnologie, 1905, 6:243; Butcher et
al., For Prod J, 1977, 27:19; Butcher et al. J For Sci, 1978,
8:403).
[0111] QACs are also widely used as skin antiseptics,
disinfectants, fabric softeners, antistatic agents, cleaning
agents, and preservatives. Detergent properties and antimicrobial
activities of QACs have made them useful for general environmental
sanitations, for examples, in hospitals and food production
facilities. In pharmacological preparations they are used such as
mouth rinses, lozenges, sprays and gels.
[0112] In humans and animals QACs have been considered too toxic
for systematic applications, but are accepted to be safe for
topical applications. Furthermore, QACs have recently been used as
penetration enhancers for transnasal and transbuccal drug delivery,
as well as in nasal vaccination (Klinguer et al., Vaccine, 2001,
19:4236). This ability to penetrate and open cell membrane has been
widely used in drug delivery via liposomes (mainly QACs with two
long alkyl chains) and non-viral gene delivery (Liu and Huang, J
Contr Rel, 2002, 78:259). Many examples of compounds having
nitrogen atoms, which exist as quaternary ammonium species or can
be converted into quaternary ammonium species, are disclosed
herein.
[0113] In some examples, when the cation is a quaternary ammonium
compound, the anion is not an inorganic anion, examples of which
are disclosed herein. In other examples, where the cation is a
quaternary ammonium compound, the anion is not a halide.
Aliphatic Heteroaryls
[0114] Some specific QACs suitable for use herein are aliphatic
heteroaryls. An aliphatic heteroaryl cation is a compound that
comprises an aliphatic moiety bonded to a heteroaryl moiety, in the
aliphatic heteroaryl cation, the aliphatic moiety can be any alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkenyl group, as described
herein. Generally, the aliphatic moiety can comprise at least 10,
at least 12, at least 14, at least 16, at least 18, or at least 20
carbon atoms. In other examples, the aliphatic moiety can comprise
a mixture of aliphatic groups having a range of carbon atoms. For
example, the aliphatic moiety can comprise from 10 to 40, from 12
to 38, from 14 to 36, from 16 to 34, from 18 to 32, from 14 to 18,
or from 20 to 30 carbon atoms, in some specific examples, the
aliphatic moiety can contain 10, 11, 12, 13, 14, 15, 16, 17, 18,
19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,
36, 37, 38, 39, 40, 41, 42, 43, 44, or 45 carbon atoms, where any
of the stated values can form an upper or lower endpoint when
appropriate. Examples of specific aliphatic moieties that can be
used include, but are not limited to, decyl, dodecyl (lauryl),
tetradecyl (myristyl), hexadecyl (palmityl or cetyl), octadecyl
(stearyl), eicosyl (arachidyl), and linolenyl groups, including
branched derivatives thereof and any mixtures thereof. In the
aliphatic heteroaryl cations, the aliphatic moiety is bonded to a
heteroatom in the heteroaryl moiety.
[0115] In the aliphatic heteroaryl cation, the heteroaryl moiety
can be any heteroaryl moiety as described herein. For example, the
heteroaryl moiety can be an aryl group having one or more
heteroatoms (e.g., nitrogen, oxygen, sulfur, phosphorous, or
holmium). Examples of specific heteroaryl moieties that can be used
in the aliphatic heteroaryl cations include, but are not limited
to, pyrazole, pyrazine, pyrimidine, pryidazine, indolizine,
isoindole, indole, indazole, imidazole, oxazole, triazole,
thiazole, purine, isoquinoline, quinoline, phthalazine,
quinooxaline, phenazine, and the like, including substituted
derivatives and mixtures thereof. In the aliphatic heteroaryl
cations, a heteroatom in the heteroaryl moiety is bonded to the
aliphatic moiety. When the heteroatom of the heteroaryl is
nitrogen, this forms a quaternary ammonium cation, as described
herein.
[0116] Further examples of aliphatic heteroaryl cations are those
having the following structures:
##STR00001##
wherein R.sup.1 and R.sup.2 are, independently, a C.sub.1-C.sub.6
alkyl group or a C.sub.1-C.sub.6 alkoxyalkyl group, and R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9
(R.sup.3-R.sup.9), when present, are independently H, a
C.sub.1-C.sub.6 alkyl, a C.sub.1-C.sub.6 alkoxyalkyl group, a
C.sub.1-C.sub.6 alkoxy group, or an energetic substituents such as
nitro, amino, cyano, azido, alkyl nitro, alkyl amino, alkyl cyano,
alkyl azido, alkoxy nitro, alkoxy amino, alkoxy cyano, and alkoxy
azido. In other examples, both R.sup.1 and R.sup.2 groups are
C.sub.1-C.sub.4 alkyl, with one being methyl, and R.sup.3-R.sup.9,
when present, are H. Exemplary C.sub.1-C.sub.6 alkyl groups and
C.sub.1-C.sub.4 alkyl groups include methyl, ethyl, propyl,
iso-propyl, butyl, sec-butyl, iso-butyl, pentyl, iso-pentyl, hexyl,
2-ethylbutyl, 2-methylpentyl, and the like. Corresponding
C.sub.1-C.sub.6 alkoxy groups contain the above C.sub.1-C.sub.6
alkyl group bonded to an oxygen atom that is also bonded to the
cation ring. An alkoxyalkyl group contains an ether group bonded to
an alkyl group, and here contains a total of up to six carbon
atoms. It is to be noted that there are two isomeric
1,2,3-triazoles. In some examples, all R groups not required for
cation formation can be H.
[0117] The phrase "when present" is often used herein in regard to
substituent R group because not all cations have all of the
numbered R groups. All of the contemplated cations contain at least
four R groups, which can be H, although R.sup.2 need not be present
in all cations.
[0118] In one example, all R groups that are not required for
cation formation; i.e., those other than R.sup.1 and R.sup.2 for
compounds other than the imidazolium, pyrazolium, and triazolium
cations shown above, are H.
[0119] A cation that contains a single five-membered ring that is
free of fusion to other ring structures is suitable for use herein.
Exemplary cations are illustrated below wherein R.sup.1, R.sup.2,
and R.sup.3-R.sup.5, when present, are as defined before.
##STR00002##
[0120] Of the cations that contain a single five-membered ring free
of fusion to other ring structures, an imidazolium cation that
corresponds in structure to Formula A is also suitable, wherein
R.sup.1, R.sup.2 and R.sup.3-R.sup.5, are as defined before.
##STR00003##
[0121] In a further example, an N,N-1,3-di-(C.sub.1-C.sub.6
alkyl)-substituted-imidazolium ion can be used; i.e., an
imidazolium cation wherein R.sup.3-R.sup.5 of Formula A are each H,
and R.sup.1 and R.sup.2 are independently each a C.sub.1-C.sub.6
alkyl group or a C.sub.1-C.sub.6 alkoxyalkyl group. In yet another
example, the cation illustrated by a compound that corresponds in
structure to Formula B, below, wherein R.sup.3-R.sup.5 of Formula A
are each hydrogen and R.sup.1 is a C.sub.1-C.sub.6-alkyl group or a
C.sub.1-C.sub.6 alkoxyalkyl group.
##STR00004##
[0122] The disclosed ionic liquid compositions can also comprise an
aliphatic benzylalkyl ammonium cation. An aliphatic benzylalkyl
ammonium cation is a cation that comprises an aliphatic moiety
bonded to the nitrogen atom of a benzylalkyl amine moiety. The
aliphatic moiety can be as described herein. The benzylalkyl amine
moiety can be a benzyl amine where the amine is bonded to an alkyl
or cyclic alkyl group, as described herein. One or more types of
aliphatic benzylalkyl ammonium cation can be used in the ionic
liquid compositions disclosed herein. The aliphatic benzylalkyl
ammonium cation suitable for use herein can be prepared by methods
known in the art or can be obtained from commercial sources.
[0123] In one aspect, the aliphatic benzylalkyl ammonium cation can
be represented by the following formula:
##STR00005##
wherein R.sup.10 is an aliphatic group, as described above,
R.sup.11 and R.sup.12 are, independent of one another, alkyl groups
or cyclic alkyl groups as described herein. In some examples, one
or more of the "R" substituents can be a long chain alkyl group
(e.g., the number of carbon atoms is 10 or greater). In other
examples, one or more of the "R" substituents can be a short chain
alkyl group (e.g., the number of carbon atoms is less than 10). In
still other examples, one of the "R" substituents is a long chain
alkyl group and the other two "R" substituents are short chain
alkyl groups.
[0124] In one aspect, the aliphatic benzylalkyl ammonium cation can
have any of the aliphatic moieties disclosed herein bonded to any
benzylalkyl amine moieties disclosed herein. In some specific
examples, R.sup.10 in the formula of aliphatic benzylalkyl ammonium
cation can be an aliphatic group of from 10 to 40 carbon atoms,
e.g., a decyl, dodecyl (lauryl), tetradecyl (myristyl), hexadecyl
(palmityl or cetyl), octadecyl (stearyl), or eicosyl (arachidyl)
group, and R.sup.11 and R.sup.12 can each be, independent of one
another, a methyl, ethyl, propyl, butyl, pentyl, or hexyl
group.
[0125] In another aspect, the aliphatic benzylalkyl ammonium cation
can include, but are not limited to, alkyl dimethyl benzyl ammonium
cations. Specific examples of alkyl dimethyl benzyl ammonium
cations include, but are not limited to, cetyl dimethyl benzyl
ammonium, lauryl dimethyl benzyl ammonium, myristyl dimethyl benzyl
ammonium, stearyl dimethyl benzyl ammonium, and arachidyl dimethyl
benzyl ammonium.
[0126] In yet another aspect, the aliphatic benzylalkyl ammonium
cation can include, but are not limited to, alkyl methylethyl
benzyl ammonium cations. Specific examples of alkyl methylethyl
benzyl ammonium cations include, but are not limited to, cetyl
methylethyl benzyl ammonium, lauryl methylethyl benzyl ammonium,
myristyl methylethyl benzyl ammonium, stearyl methylethyl benzyl
ammonium, and arachidyl methylethyl benzyl ammonium.
Dialiphatic Dialkyl Ammonium
[0127] Still further examples of QACs that can be used in the
disclosed ionic liquid compositions are dialiphatic dialkyl
ammonium cations. A dialiphatic dialkyl ammonium cation is a
compound that comprises two aliphatic moieties and two alkyl
moieties bonded to a nitrogen atom. The aliphatic moieties can be
the same or different and can be any aliphatic group as described
above. The alkyl moieties can be the same or different can be any
alkyl group as described above. In the disclosed dialiphatic
ammoniums cations, the two aliphatic moieties can have 10 or more
carbon atoms and the two alkyl moieties can have less than 10
carbon atoms. In another alternative, the two aliphatic moieties
can have less than 10 carbon atoms and the two alkyl moieties can
have 10 or more carbon atoms.
[0128] One or more types of dialiphatic dialkyl ammonium cations
can be used in the ionic liquid compositions disclosed herein.
[0129] In some particular examples, the dialiphatic dialkyl
ammonium cation can be di-dodecyl dimethyl ammonium, di-tetradecyl
dimethyl ammonium, dihexadecyl dimethyl ammonium, and the like,
including combinations thereof.
Tetraalkyl Ammonium
[0130] The disclosed ionic liquid compositions can also comprise a
tetraalkyl ammonium cation. Suitable tetraalkyl ammonium cations
comprise four alkyl moieties, as disclosed herein. In one example,
a tetraalkyl ammonium cation can comprise one long chain alkyl
moiety (e.g., 10 or more carbon atoms in length) and three short
chain alkyl moieties (e.g., less than 10 carbon atoms in
length).
[0131] Some specific examples of tetraalkyl ammonium cations that
can be included in the disclosed ionic liquid compositions include,
but are not limited to, cetyl trimethyl ammonium, lauryl trimethyl
ammonium, myristyl trimethyl ammonium, stearyl trimethyl ammonium,
arachidyl trimethyl ammonium, or mixtures thereof. Other examples
include, but are not limited to, cetyl dimethylethyl ammonium,
lauryl dimethylethyl ammonium, myristyl dimethylethyl ammonium,
stearyl dimethylethyl ammonium, arachidyl dimethylethyl ammonium,
or mixtures thereof.
Other Cations
[0132] Other cations that are suitable for use in the disclosed
methods and compositions are compounds that contain metals.
According to the methods and compositions disclosed herein, any
compound that contains a metal atom can be a suitable cation.
Organometallic compounds or metal complexes commonly have one or
more metal atom in a positive oxidation state. Examples of metals
that can be present in a suitable cation include, but are not
limited to, lithium, sodium, potassium beryllium, magnesium,
calcium, strontium, chromium, manganese, iron, cobalt, nickel,
copper, and zinc. Silver nanoparticles can also be used. Examples
of suitable organometallic cations include, but are not limited to,
metallocenium, alkylgermanyl, alkyltin, or alkylsilyl (e.g.,
trimethylsilylium, triethylsilylium, tris(trimethylsilyl)silylium,
tribenzylsilylium, triphenylsilylium, tricyclohexylsilylium, and
dimethyloctadecylsilylium).
[0133] Another suitable group of quaternary ammonium cations are
those that have been prepared by esterifying a compound containing
a carboxylic acid moiety or transesterifying a compound with an
ester moiety with a choline moiety. Such choline esters cart be
biofriendly, permanent ions that are amenable to being added to
various compounds while still being easily cleavable under
physiological conditions. The choline esters can be used to
increase the solubility and bioavailability of many neutral
compounds.
[0134] Further examples of cations include
(2-hydroxyethyl)-dimethylundecyloxymethylammonium,
(2-acetoxyethyl)-heptyloxymethyldimethylammonium, and
(2-acetoxyethyl)-dodecyloxymethyldimethylammonium, mepenzolate,
sulfathiazole, thimerosal, and valproic acid.
[0135] In other examples, the cation can be an energetic cation as
disclosed in Katritzky et al., "ILs Based on Energetic Imadazolium
Cations: Nitro- and Nitrile-substituted N,N' Dialkylimidazolium
Salts" New J Chem 30:349, 2006, which is incorporated by reference
herein at least for its teachings of energetic ions.
[0136] Anions
[0137] Particular examples of anionic compounds that can be present
in the disclosed ionic liquids are compounds that contain oxygen
atoms. Oxygen atoms can exist or can be converted to negatively
charged, anionic species, for example, through deprotonation of
alcohols or acids, through saponification of esters, or through
alkylation of ketones. Likewise, compounds that contain sulfur
atoms can also exist or be converted to anionic species through
similar reactions. Still further, compounds that contain nitrogen
atoms, especially nitrogen atoms adjacent to electron withdrawing
groups or resonance stabilizing structures, can be converted to
anions through deprotonation. According to the methods and
compositions disclosed herein, any compound that contains an
oxygen, sulfur, or nitrogen atom can be a suitable anion for the
disclosed ionic liquid compositions.
[0138] Other suitable anions include, but are not limited to,
halides (e.g., fluoride, chloride, bromide, and iodide), sulfates
(SO.sub.4.sup.-), carbonates, bicarbonates, phosphates, phosphates,
nitrates (NO.sub.3.sup.-), nitrites (NO.sub.2.sup.-), acetates
(CH.sub.3CO.sub.2.sup.-), and the like. Other examples of anions
include, but are not limited to PF.sub.6.sup.- that is immiscible
in water and BF.sub.4.sup.- that is miscible in water depending on
the ratio of ionic liquid to water, system temperature, and alkyl
chain length of cation. Other anions include triflate (TfO;
CF.sub.3SO.sub.2.sup.-), nonaflate (NfO;
CF.sub.3(CF.sub.2).sub.3SO.sub.2.sup.-), bis(triflyl)amide
(Tf.sub.2N; (CF.sub.3SO.sub.2).sub.2N.sup.-), trifluoroacetate (TA;
CF.sub.3CO.sub.2.sup.-), and heptafluororobutanoate (HB;
CF.sub.3(CF.sub.2).sub.3SO.sub.2.sup.-). Other types of ionic
liquids include haloaluminates, such as chloroaluminate.
[0139] Other suitable anions contemplated herein are saccharin and
acesulfame. Saccharin, as an alkali metal salt, and acesulfame
(6-methyl-3,4-dihydro-1,2,3-oxathiazin-4-one 2,2-dioxide), which
has previously only been offered as potassium salt, are in
widespread use in foodstuffs as non-nutritive sweeteners. Such
anions can be used when one desires to prepare an ionic liquid
composition that has sweetness as one of its desired properties.
For example, saccharin and acesulfame can be combined with
pharmaceutically active cations to prepare sweet tasting ionic
liquids that have pharmaceutical activity.
[0140] Specific examples of other anions include piperacillin,
folic acid, ibuprofen, fast green FCF, docusate, acesulfamate,
penicillin G, Colawet MA-80, salicylic acid, saccharinate,
sulfacetamide, naproxen, benzoate, diclofenac, and trans-cinnamic
acid.
[0141] Other suitable anions include, but are not limited to,
substituted and un-substituted imidazolates, 1,2,3-triazolates, and
1,2,4-triazolates, benzimidazolates, triazolates, as shown
bellow:
##STR00006##
wherein R.sup.13, R.sup.14, R.sup.16, R.sup.17, (R.sup.13-17), when
present, are independently H, a C.sub.1-C.sub.6 alkyl, a
C.sub.1-C.sub.6 alkoxyalkyl group, a C.sub.1-C.sub.6 alkoxy group,
or energetic substituents like nitro, amino, cyano, azido, alkyl
nitro, alkyl amino, alkyl cyano, alkyl azido, alkoxy nitro, alkoxy
amino, alkoxy cyano, and alkoxy azido. Exemplary C.sub.1-C.sub.6
alkyl groups and C.sub.1-C.sub.4 alkyl groups include methyl,
ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl, pentyl,
iso-pentyl, hexyl, 2-ethylbutyl, 2-methylpentyl, and the like.
Corresponding C.sub.1-C.sub.6 alkoxy groups contain the above
C.sub.1-C.sub.6 alkyl group bonded to an oxygen atom that is also
bonded to the cation ring. An alkoxyalkyl group contains an ether
10 group bonded to an alkyl group, and here contains a total of up
to six carbon atoms. It is to be noted that there are two isomeric
1,2,3-triazoles. In some examples, all R groups not required for
anion formation can be H.
[0142] Further examples of suitable energetic anions are disclosed
in Katritzky et al., "ILs Based on Energetic Azolate Anions," Chem
Eur J 12:4630, 2006, which is incorporated by reference herein at
least for its teachings of energetic anions.
Compound that Exist that as Both: Anion or Cation
[0143] Examples of compounds that exist as cations in some
environments and anions in other environments include, but are not
limited to, 1,3-dimethylimidazolium, 1-butyl-3-methylimidazolium,
1,2,3-triazolium, tetrazolium, 1,2,4-triazolium,
1,3-dimethyl-1,2,3-triazolium, and 1,3-dimethyl-4-nitroimidazolium,
which exist as a cations, and 4-nitroimidazolate,
4,5-dinitroimidazolate, 3,5-dinitro-1,2,4-triazolate, tetrazolate,
5-aminotetrazolate, 2-nitroimidazolate, which exist as an anion.
Those separate ions can still form single product ionic
liquids.
[0144] Examples of compounds that can change from an anion in one
environment to a cation in another environment due to chemical
modifications are the sulfur ylides through the reaction of a
sulfide with methyliodide to form the sulfonium ion.
Specific Examples of Pharmaceutical Actives
[0145] When pharmaceutical activity is a desired property of the
disclosed ionic liquids, one or more of the ions in the disclosed
ionic liquid compositions can be a pharmaceutical active.
Pharmaceutical actives that exist as ions or can be converted to
ions, and which are suitable for use in preparing the disclosed
ionic liquid compositions, include the following categories and
specific examples, it is not intended that the category be limited
by the specific examples. Those of ordinary skill in the art will
be able to readily identify those pharmaceutical actives that can
be used in the disclosed methods and compositions. For example, one
can identify a compound with a given property or activity by
consulting various sources, such as the Merck Index (13.sup.th
Edition, Wiley, 2001). The United States Pharmacopeia-National
Formulary (USP-NF), and the FDA's Orange book, which are each
incorporated by reference herein at least for their teachings of
pharmaceutical actives. Once a compound with a desired property is
identified, the skilled artisan can determine whether the compound
is ionic or can be made ionic. Such determinations can be performed
based on the compound's structure, which can readily be determined
by consulting the sources mentioned herein or experimentally.
Knowing a compound's structure can readily reveal if the compound
is ionic, in fact, many pharmaceutical actives exist as salts and
are thus suitable for use in preparing the disclosed ionic liquid
compositions. Further, if a compound is not ionic, but contains an
ion forming moiety (e.g., nitrogen, oxygen, sulfur, or metal atoms,
as described herein), the compound can be converted to an ion and
then combined with a suitable counterion to prepare the disclosed
ionic liquid compositions. Those of ordinary skill in the on will
recognize numerous other compounds that fall within the categories
and that are useful according to the disclosed compositions and
methods.
[0146] Some specific examples of pharmaceutical actives that can be
used in the disclosed ionic liquids include, but are not limited
to, aspirin, LIBRIUM.TM., isoniazid, PRONTOSIL.TM., cisplatin,
6-mercaptopurine, RITUXAN.TM., TAXOL.TM., phenobarbital,
PROZAC.TM., ALLEGRA.TM., VIOXX.TM., quinine, ivermectin, L-dopa,
THORAZINE.TM., salvarsan, TAGAMET.TM., AZT, crixivan, salbutamol,
digoxin, fluride, LOVASTATIN.TM., erythropoietin, hydrocortisone,
insulin, oral contraceptives, oxytocin, PREMARIN.TM., RU-486,
thyroxine, thalidomide, cyclosporine, fentanyl, methadone,
morphine, botox, vitamins, FOSAMAX.TM., RITALIN.TM., and
VIAGRA.TM., including ionic derivatives thereof.
[0147] Other examples of pharmaceutical active ions or
pharmaceutical actives that can be made ionic include, but are not
limited to, pantoprazole, sold under the trade names PROTONIX.TM.
and PANTOZOL.TM., and rabeprazole, sold under the trade names
ACIPHEX.TM. and PARIET.TM., which are used to treat
gastrointestinal disorders. Risedronate, sold under the trade name
ACTONEL.TM., and alendronate, sold under the trade name
FOSAMAX.TM., are used to treat osteoporosis and are further
examples of suitable compounds that can be used to prepare the
disclosed ionic liquid compositions. Further examples include
losartan, sold under the trade names NU-LOTAN.TM., COZAAR.TM., and
HYZAAR.TM., and fosinopril, sold under the trade name MONOPRIL.TM.,
which are used to treat hypertension and are other examples of
suitable compounds that can be used to prepare the disclosed ionic
liquid compositions. Atorvastatin, sold under the trade name
LIPITOR.TM., and pravastatin, sold under the trade name
PRAVACHOL.TM., are used to treat cholesterol and are further
examples of suitable compounds that can be used to prepare the
disclosed ionic liquid compositions. A further example is
montelukast, which is used to treat asthma and is sold under the
trade name SINGULAIR.TM..
[0148] The following table illustrates further examples of
pharmaceutical actives that are ionic or can be made ionic and
combined with other ions to form the disclosed ionic liquid
compositions.
TABLE-US-00001 TABLE 1 Name Compound MP Patent No. Other Names
Function: Abortifacient/Interceptive Prostaglandin E.sub.2
##STR00007## 66-68.degree. U.S. Pat. No. 3,598,858 PGE2, U-12062,
Cerviprost, Minprostin E2, Prepidil, Propess, Prostarmon-E, Prostin
E2 Prostaglandin F2.sub.A ##STR00008## 25-35.degree. U.S. Pat. No.
3,657,327 PGF2A, U-14583 Enzaprost F, Glandin, Prostarmon F
Sulprostone ##STR00009## U.S. Pat. No. 4,024,179 Nalador Function:
ACE- Inhibitor (Antihypertensive) Cetapril ##STR00010##
155-156.degree. U.S. Pat. No. 4,248,883 Alacepril Benzaepril
##STR00011## 148-149.degree. U.S. Pat. No. 4,410,520 Captopril
##STR00012## 103-104.degree. U.S. Pat. Nos. 4,046,889 4,105,776
Acediur, Acepril, Alopresin, Acepress, Capoten, Captolane,
Captoril, Cesplon, Dilabar, Garranil, Hipertil, Lopirin, Lopril,
Tensobon, Tensoprel Function: A-Adrenergic Agonist Methyl
hexaneamine ##STR00013## U.S. Pat. Nos. 2,350,318 2,386,273
Forthane Synephrine ##STR00014## 184-185.degree. DE 566578
Analeptin, Ethaphene, Oxedrine, Parasympatol, Simpalon, Synephrin,
Synthenale Function: B-Adrenergic Agonist Isoetharine ##STR00015##
212-213.degree. DE 638650 Win -3046, Dilabron, Neoisuprel
Methoxyphenamine ##STR00016## 97-99.degree. JP 612921 Function:
A-Adrenergic Blocker Tamsulosin ##STR00017## 228-230.degree. U.S.
Pat. No. 4,703,063 Flornaz, Harnali, Omnic, Pradif Tolazoline
##STR00018## 174.degree. U.S. Pat. No. 2,161,938 Lambral, Priscol,
Priscoline, Vasco- Dilatan Function: B-Adrenergic Blocker Bufuralol
##STR00019## 146.degree. U.S. Pat. No. 3,929,836 Angium Nadoxolol
##STR00020## 188.degree. U.S. Pat. No. 3,819,702 Bradyl Function:
Analgesic (non-narcotic) Acetylsalicyl salicylic acid ##STR00021##
154.degree. Ammonium Salicylate ##STR00022## Function: Anesthetic
(Intravenous) Buthalital Sodium ##STR00023## Baytinal, Buthaliton
Sodium Thialisobumalnatrium, Transithal, Ulbreval Thiopental Sodium
##STR00024## U.S. Pat. Nos. 2,153,729 2,876,225 3,109,001 Function:
Anesthetic (Local) Isobutyl p- Aminobenzoate ##STR00025##
65.degree. Cycloform, Isobutyl Kelofom, Isocaine Phenol
##STR00026## Function: Anorexic Clortermine ##STR00027##
116-118.degree. U.S. Pat. No. 3,415,937 Fenproporex ##STR00028##
126-127.degree. U.S. Pat. No. 3,485,924 Function: Antacid Dermatol
##STR00029## Function: Anthelmintic (Cesodes) Niclosamide
##STR00030## 225-230.degree. U.S. Pat. No. 3,079,297 3,113,067
Pelletierine ##STR00031## Punicine Function: Anthelimintic
(Nematodes) Dithiazanine Iodide ##STR00032## U.S. Pat. No.
2,412,815 Anelmid, Anguifugan, Delvex, Dejo, Deselmine, Dilombrin,
Dizan, Nectocyd, Partel, Telmicid, Telmid Thiabendazole
##STR00033## 304-305.degree. U.S. Pat. No. 3,017,415 Thibenzole,
Equizole, Mertect, Storite TBZ, Tecto Function: Anthelmintic
(Schistosoma) Antimony Sodium Thioglycolate ##STR00034## Niridazole
##STR00035## 260-262.degree. BE 632989 Ba-32644, Ciba 32644-Ba,
Ambilnar Function: Antiacne Isotretinoin ##STR00036##
174-175.degree. U.S. Pat. No. 4,556,518 Accitame, Isotrex, Oratane,
Roaccutane Function: Antiallergic Lodoxamide ##STR00037##
212.degree. U.S. Pat. No. 3,993,679 Ramatroban ##STR00038##
134-135.degree. U.S. Pat. No. 4,965,258 Function: Antialopecia
Agent Finasteride ##STR00039## ~257.degree. U.S. Pat. No. 4,760,071
Chibro-Proscar, Finasid, Propecia, Proscar, Prostide Minoxidil
##STR00040## 248.degree. U.S. Pat. Nos. 3,382,247 3,644,364
Alopexil, Alostil, Loniten, Lonolox, Minoximen, Normoxidil,
Prexidil, Regaine, Rogaine, Tricoxidil Function: Antiamebic
Carbarsone ##STR00041## 174.degree. JP 584418 Amabevan, Ameban,
Amibiarson, Arsambide, Carb-O- Selo, Histocarb, Fenarsone,
Leucarsone, Aminarsone, Amebarsone Diphetarsone ##STR00042##
Amebarsin, Bemarsal, Rodameb Function: Antiandrogen Flutamide
##STR00043## 111.5-112.5.degree. U.S. Pat. No. 3,847,988 Drogenil,
Eulexin, Euflex, Flucinom, Flutamin, Fugerel Nilutamide
##STR00044## 149.degree. U.S. Pat. No. 4,097,578 RU-23908,
Anandron, Nilandron Function: Antianginal Nicorandil ##STR00045##
92-93.degree. U.S. Pat. No. 4,200,640 Adancor, Ikorel, Perisalol,
Sigmart Ozagrel ##STR00046## 223-224.degree. Function:
Antiarrhythmic Bunitrolol ##STR00047## 163-165.degree. U.S. Pat.
No. 3,541,130 Ipratropium Bromide ##STR00048## 230-232.degree. U.S.
Pat. No. 3,505,337 Atem, Atrovent, Bitrop, Itrop, Narilet, Inatec
Function: Anti-arteriosclerotic Pyridinol Carbamate ##STR00049##
136-137.degree. Anginin, Angioxione, Aterosan, Atover, Cicloven,
Colesterinex, Duvaline, Morecil, Prodectin, Ravenil, Sospitan,
Vasagin, Vasapril, Vasocil, Vasoverin Function:
Antiarthritic/Antiheumatic Bucillamine ##STR00050## 139-140.degree.
U.S. Pat. No. 4,305,958 Rimatil Diacerein ##STR00051##
271-218.degree. U.S. Pat. No. 4,244,968 Artrodar, Fisiodar
Function: Antiasthmatic (Non-bronchodilator) Amlexanox ##STR00052##
>300.degree. U.S. Pat. No. 4,143,042 Aphthasol, Elics, Solfa
Cromolyn ##STR00053## Aarane, Alercrom, Alerion, Allegocrom,
Colimune, Cromoret, Firent, Gastro frenal, Inostral, Intal, Introl,
Irtan Lomudal, Lomupren, Lomusol, Lomuspray, Nalcrom, Nalcron,
Nasalcrom, Nasmil, Opticrom, Opticron, Rynacrom, Sofro, Vicrom,
Vividrin Function: Antibacterial (Antibiotics) Azidamfenicol
##STR00054## 107.degree. U.S. Pat. No. 2,882,275 Berlicetin,
Leukomycin-N, Posifenicol, Thilocanfol Thiamphenicol ##STR00055##
164.3-166.3.degree. U.S. Pat. No. 2,759,927 2,759,970 2,759,971
2,759,972 2,759,976 Hyrazin, Igralin, Neomyson, Rigelon, Thiamcol,
Thionicol, Thiophenicol, Urfamycine, Urophenil Function:
Antibacterial (Synthetic) Brodimoprim ##STR00056## 225-228.degree.
U.S. Pat. No. 4,024,145 Hyprim, Unitrim Tetroxoprim ##STR00057##
153-156.degree. U.S. Pat. No. 3,992,379 Function: Antibacterial
(Leprostatic) Acetosulfone Sodium ##STR00058## ~285.degree. U.S.
Pat. No. 2,358,365 Dapsone ##STR00059## 175-176.degree. FR 829926
Avlosulfon, Croysulfone, Diphenasone, Disulone, Dumitone, Eporal,
Novophone, Sulfona-Mae, Sulphadione, Udolac Function: Antibacterial
(Tuberculostatic) Benzoylpas ##STR00060## 260-261.degree. GB 676363
Cyamelide ##STR00061## Function: Anticoagulant Picotamide
##STR00062## 124.degree. U.S. Pat. No. 3,973,026 Function:
Anticonvulsant Acetylpheneturide ##STR00063## 100-101.degree. U.S.
Pat. No. 3,110,728 Crampol Albutoin ##STR00064## 210-211.degree.
Euprax Function: Antidepressant Caroxazone ##STR00065##
203-205.degree. U.S. Pat. No. 3,427,313 Timostenil Indalpine
##STR00066## U.S. Pat. No. 4,064,255 Upstene Function: Antidiabetic
Calcium Mesoxalate ##STR00067## Dec. 210-220.degree. C. JP 524157
JP 607463 Mesoxan Buformin ##STR00068## U.S. Pat. No. 2,961,377
Function: Antidiarrheal Alkofanone ##STR00069## Dec.
221-223.degree. U.S. Pat. No. 2,421,836 Alfone Metformin
##STR00070## U.S. Pat. No. 3,174,901 DMG5, LA-6023 Function:
Antidote (Curare) Edrphomium Chloride ##STR00071## Dec.
162-163.degree. U.S. Pat. No. 2,647,924 Antirex, Enlon, Reversol,
Tensiolon Neostigmine ##STR00072## Dec. ~167.degree. U.S. Pat. No.
1,905,990 Function: Antidote (Cyanide) p-Aminopropiophenon
##STR00073## 140.degree. DMSO Methylene Blue ##STR00074## Function:
Antidote (Folic Acid Antagonists) Folinic Acid ##STR00075## Dec.
240-250.degree. U.S. Pat. No. 2,741,608 Function: Antidote (Heavy
Metal Poisoning) Tiopronin ##STR00076## 95-97.degree. Acadione,
Capen, Epatiol, Mucolysin, Thiola, Thiosol Function: Antidote
(Methanol and Ethylene Glycol Poisoning) Fomepizole ##STR00077##
15.5-18.5.degree. Function: Antidote (Organophophate poisoning)
Asoxime Chloride ##STR00078## 145-147.degree. U.S. Pat. No.
3,773,775 Obidoxime Chloride ##STR00079## Syn: 235-236.degree.
Anti: 218-220.degree. U.S. Pat. No. 3,137,702 Toksobidin, Toxogonin
Function: Antidyskinetic Chloride ##STR00080## 130.degree. U.S.
Pat. No. 3,202,660 Tiapride ##STR00081## 123-125.degree. C. GB
1394563 Function: Antiemetic Alizapride ##STR00082## 139.degree.
U.S. Pat. No. 4,093,672 Bromopride ##STR00083## U.S. Pat. No.
3,177,252 Emepride, Emoril, Viadil
Function: Antifibrotic Potassium p- Aminobenzoate ##STR00084##
Potaba Function: (synthetic) Chlordantoin ##STR00085## Bromo-
salicylchloranilide ##STR00086## 238-243.degree. U.S. Pat. No.
2,802,029 Multifungin Function: Antiglaucoma Acetazolamide
##STR00087## 258-259.degree. U.S. Pat. No. 2,554,816 Acetamox,
Atenezol, Defiltran, Diamox, Didoc, Diuriwas, Donmox, Edemox,
Fonurit, Glaupax Benfunolol ##STR00088## 160.degree. U.S. Pat. No.
3,470,194 Versus, Zildasac Function: Antigout Allopurinol
##STR00089## above 360.degree. U.S. Pat. No. 3,474,098 Carprofen
##STR00090## 197-198.degree. U.S. Pat. No. 3,896,145 Imadyl,
Rimadyl Function: Antihistaminic Acrivastine ##STR00091## Dec.
222.degree. U.S. Pat. No. 4,501,893 Semprex Metron S ##STR00092##
84-85.degree. Function: Anti-hyperlipoproteninemic Acifran
##STR00093## 176.degree. U.S. Pat. No. 4,244,958 Reductol
Benfluorex ##STR00094## U.S. Pat. No. 3,607,909 Function:
Anti-hypertensive Chlorisonclamine Cloride ##STR00095##
258-265.degree. U.S. Pat. No. 3,025,294 Ecolid, Ecolid Chloride
Pentamethonium Bromide ##STR00096## Penthonium, Lytensium Function:
Anti-hyperthyroid 2-Aminothiazole ##STR00097## 93.degree. U.S. Pat.
No. 2,242,237 Methylthio- uracil ##STR00098## Dec. 326-331.degree.
Alkiron, Antibason, Basecil, Basethyrin, Methiacil, Methicil,
Methiocil, Muracil, Prostrumyl, Strumacil, Thimecil, Thyreostat I
Function: Anti-hypotensive Amexinium Methyl Sulfate ##STR00099##
176.degree. U.S. Pat. No. 3,631,038 Regulton, Risumic, Supratonin
Dopamine Hydrochloride ##STR00100## Dec. 241.degree. Cardiosteril,
Dopastat, Dynatra, Inovan, Inotropin Function: Anti-Inflammatory
(Gastrointestinal) Balsalazide ##STR00101## >350.degree. U.S.
Pat. No. 4,412,992 Mesalamine ##STR00102## dec. 280.degree. GB
751386 Asacol, Ascolitin, Claversal, Lixacol, Mesasal, Pentasa,
Rowasa, Salofalk Function: Anti-Inflammatory (Nonsteroidal)
Enfenamic Acid ##STR00103## 116-117.degree. IN 103066 IN 114805
Tromaril Menfenamic Acid Flufenamic Acid Aluminum Salt ##STR00104##
Alfenamin, Opyrin Function: Antimalarial Berberine ##STR00105##
145.degree. Chloguanide ##STR00106## 129.degree. FR 1001548
Function: Antimanic Valproic Acid ##STR00107## liquid Convulex,
Depakene, Mylproin Function: Antimigraine Lisuride ##STR00108##
186.degree. Naratriptan ##STR00109## 170-171.degree. U.S. Pat. No.
4,997,841 Function: Antimuscarinic Ambutonium Bromide ##STR00110##
228-229.degree. Benzilonium Bromide ##STR00111## 203-204.degree. CP
821436 Minelsin, Minelcin, Portyn, Ulcoban Function: Antineoplastic
9-Amino- camptothecin ##STR00112## 300.degree. JP KoKai 59 51289
(to Yakult Honsha) Tenuazonic Acid ##STR00113## Function:
Antiobsessional Clometocillin ##STR00114## U.S. Pat. No. 3,007,920
Rixapen Fluoxetine Hydrochloride ##STR00115## 157-158.degree. U.S.
Pat. No. 4,314,081 Adofen, Fluctin, Fluoxeren, Fontex, Foxetin,
Lovan, Prozac, Reneuron, Sarafem Function: Antiosteoporotic
Pamidronic Acid ##STR00116## U.S. Pat. No. 4,327,039 Risedronate
Sodium ##STR00117## U.S. Pat. No. 5,583,122 Acetonel, Optinate
Function: Antiparkinsonian Benserazide Hydrochloride ##STR00118##
146-148.degree. U.S. Pat. No. 3,178,476 Carbidopa ##STR00119##
203-205.degree. U.S. Pat. No. 3,462,536 Lodosyn Function:
Antipheochromoc-ytoma Metyrosine ##STR00120## 310-315.degree. U.S.
Pat. No. 2,868,818 Demser Phentolamine ##STR00121## 174-175.degree.
U.S. Pat. No. 2,503,059 Function: Anti-pneumocystic Elfornithine
Hydrochloride monohydrate ##STR00122## 183.degree. Sulfamethoxazole
##STR00123## 167.degree. U.S. Pat. No. 2,888,455 Gantanol, Sinomin
Function: Antiprostatic Hypertrophy Tamsulosin Hydrochloride
##STR00124## 228-230.degree. U.S. Pat. No. 4,703,063 Flomax,
Harnal, Omnic, Pradif Terazosin ##STR00125## 272-274.degree. U.S.
Pat. No. 4,026,894 U.S. Pat. No. 4,251,532 Function: Antiprotozoal
Cryptosporidium Nitazoxanide ##STR00126## 202.degree. U.S. Pat. No.
3,950,351 Cryptaz Function: Antiprotozoal (Giardia) Acranil.sup.r
##STR00127## 237-238.degree. U.S. Pat. No. 2,113,357 Function:
Antiprotozoal (Leishmania) Hydroxystil- bamidine ##STR00128##
235.degree. U.S. Pat. No. 2,510,047 Pentamidine ##STR00129## dec.
186.degree. U.S. Pat. No. 2,394,003 Function: Antiprotozoal
(Toxoplasma) Pyrimethamine ##STR00130## 233-234.degree. U.S. Pat.
No. 2,680,740 Chloridin, Daraprim, Malcoide, Tindurin Function:
Antiprotozoal (Trichomonas) Acetarsone ##STR00131## 240-250.degree.
Gynoplix, Orarsan, Spirocid, Stovarsol Aminitrozole ##STR00132##
264-265.degree. U.S. Pat. No. 2,531,756 Tritheon, Trichorad,
Enheptin-A Function: Antiprotozoal (Trypanosoma) Benznidazole
##STR00133## 188-190.degree. GB 1138529 Radanil Eflornithine
Hydrochloride ##STR00134## 183.degree. Ornidyl Function:
Antipsoriatic Acitretin ##STR00135## 228-230.degree. U.S. Pat. No.
4,105,681 Neotigason, Soriatane 6-Azauridine ##STR00136##
160-161.degree. Function: Antipsychotic Amisulpride ##STR00137##
126-127.degree. U.S. Pat. No. 4,401,822 Deniban, Socian, Solian,
Sulamid Remoxipride Hydrochloride Monohydrate ##STR00138##
173.degree. U.S. Pat. No. 4,232,037 Roxiam Function: Antipyretic
Bufexamac ##STR00139## 153-155.degree. U.S. Pat. No. 3,479,396
Droxaryl, Feximac, Malipuran, Mofenar, Norfemae, Parfenac, Parfenal
Bumadizon ##STR00140## 116-117.degree. U.S. Pat. No. 3,455,999
Function: Antirickettsial Chloramphenicol ##STR00141##
150-151.degree. U.S. Pat. No. 2,839,577 Function:
Antiseptic/Disinfectant Benzoxonium Chloride ##STR00142##
107-109.degree. CH 306648 Absonal, Bactofen, Bialcol Cetalkonium
Chloride ##STR00143## 59.degree. U.S. Pat. No. 2,075,958 Banicol,
Acetoquate CDAC, Ammonyx G, Zettyn, Ammonyx T, Cetol Function:
Antispasmodic Alibendol ##STR00144## 95.degree. U.S. Pat. No.
3,668,238 Cebera Ambutonium Bromide ##STR00145## 228-229.degree.
Function: Antisyphilitic Arshpenamine ##STR00146## U.S. Pat. No.
986148 Ehrlich 606, Salvarsan Sodium Arsanilate ##STR00147##
Arsamin, Atoxyl, Nuarsol, Protoxyl, Soamin, Sonate, Piglet Pro-Gen
V, Trypoxyl Function: Antithrom-boxythemic Anagrelide ##STR00148##
>280.degree. U.S. Pat. No. 4,146,718 Agrylin Function:
Antihrombotic Beraprost ##STR00149## U.S. Pat. No. 4,474,802
Dorner, Procylin Cilostazol ##STR00150## 159-160.degree. BE 878548
Pletal Function: Antitussive Bibenzonium Bromide ##STR00151##
144-147.degree. U.S. Pat. No. 2,913,459 Sedobex, Lysobex, Lysibex,
Thoragol, Lysbex, Medipectol Sodium Dibunate ##STR00152## dec.
>300.degree. Labaz, Becantal, Becantex, Dibunafon, Keuten,
Linctussal Function: Antiulcerative Aldioxa ##STR00153##
230.degree. U.S. Pat. No. 2,761,867 Alanetorin, Alusa, Arlanto,
Ascomp, Chlokale, Isalon, Nische, Peptilate Cimetidine ##STR00154##
141-143.degree. U.S. Pat. No. 3,950,333 Acibilin, Acinil, Cimal,
Cimetag, Cimetum Edalene, Dyspamet, Eureceptor, Gastromet, Peptol
Function: Antiurolithic Allopurinol ##STR00155## >350.degree.
U.S. Pat. No. 3,474,098 Succinimide ##STR00156## 125-127.degree.
Orotric Function: Antiviral Foscarnet Sodium ##STR00157##
>250.degree. U.S. Pat. No. 4,215,113 Foscavir Efavirenz
##STR00158## 139-141.degree. U.S. Pat. No. 5,519,021 Function:
Anxiolytic Etifoxine ##STR00159## 90-92.degree. U.S. Pat. No.
3,725,404 Valnoctamide ##STR00160## 113-114.degree. Axiquel,
Nirvanil Function: Atriopeptidase Inhibitor Cannabinol ##STR00161##
76-77.degree. Function: Bronchodilator Oxitropium Bromide
##STR00162## 203-204.degree. U.S. Pat. No. 3,472,861 Oxivent,
Tersigat, Ventilat Tiotropium Bromide ##STR00163## 218-220.degree.
EP 418716 Function: Calcium Channel Blocker Fendiline Hydrochloride
##STR00164## 204-205.degree. U.S. Pat. No. 3,262,977 Cordan,
Fendilar, Sensit Prenylamine ##STR00165## 36-37.degree. U.S. Pat.
No. 3,152,173 Elecor
Function: Carbonic Anhydrase Inhibitor Acetazolamide ##STR00166##
258-259.degree. U.S. Pat. No. 2,554,816 Acetamox, Atenezol, Diamox,
Didoc, Diuriwas, Donmox, Edemox, Fonurit, Glaupax Flumethiazide
##STR00167## 305-307.degree. U.S. Pat. No. 3,040,042 Ademol,
Fludemil Function: Cardioprotective Acadesine ##STR00168##
213-214.degree. Arasine, Protara Cariporide ##STR00169##
90-94.degree. U.S. Pat. No. 5,591,754 Function: Cardotonic
Levosimendan ##STR00170## 210-214.degree. U.S. Pat. No. 5,569,657
Simdax Pimobendan Hydrochloride ##STR00171## 311.degree. U.S. Pat.
No. 4,361,563 Function: Cholelitholytic Agent Ursodiol ##STR00172##
203.degree. Actigall, Arsacol, Cholit-Ursan, Delursan, Desol,
Destolit, Deursil, Litursol, Lyeton, Peptarom, Solutrat, Urdes,
Ursacol, Urso, Ursochol, Ursofalk, Ursolvan. Chenodiol ##STR00173##
119.degree. Chendol, Chenix, Chenocedon, Chenocol, Chenodex,
Chenofaulk, Chenossil, Chenosaure, Cholanorm, Fluibil, Hekbilin,
Ulmenide Function: Choleretic Cholic Acid Monohydrate ##STR00174##
198.degree. Colalin Clanobutin ##STR00175## 115-116.degree. U.S.
Pat. No. 3,780,095 Bykahepar Function: Cholinergic Echothiophate
Iodide ##STR00176## 138.degree. U.S. Pat. No. 2,911,430 Edrophonium
Chloride ##STR00177## 162-163.degree. U.S. Pat. No. 2,647,924
Antirex, Enlon, Eversol, Tensilon Function: Cholinesterase
Inhibitor Ambenonium Chloride ##STR00178## 196-199.degree. DE
1024517 Mytelase Distigmine Bromide ##STR00179## dec 143.degree.
U.S. Pat. No. 2,789,981 Ubretide Function: Cholinesterase
Reactivator Asoxime Chloride ##STR00180## 145-147.degree. U.S. Pat.
No. 3,773,775 Obidoxime Chloride ##STR00181## dec 225.degree. U.S.
Pat. No. 3,137,702 Toksobidin, Toxogonin Function: CNS Stimulant
Pemoline ##STR00182## 256-257.degree. U.S. Pat. No. 2,892,753
Azoksodon, Cylert, Deltamine, Hyton Asa, Kethamed, Nitan, Pioxol,
Pondex, Senior, Sigmadyn, Stimul, Tradon, Volital Phenmetrazine
##STR00183## liquid U.S. Pat. No. 2,835,669 Function:
Cyclooxygenase-2 Inhibitor Celecoxib ##STR00184## 157-159.degree.
WO 95 15316 Celebrex Function: Cytoprotectant (Gastric) Cetraxate
##STR00185## 200-280.degree. U.S. Pat. No. 3,699,149 Irsogladine
##STR00186## 268-269.degree. U.S. Pat. No. 3,966,728 Function:
Decongestant Naphazoline Hydrochloride ##STR00187## 255-260.degree.
U.S. Pat. No. 2,161,938 Ak-con, Albalon, Clera, Coldan, Iridina,
Naphcon, Niazol, OpconRhinantin, Phinoperd, Sanorin, Sanorin-Spofa,
Strictylon Nordefrin Hydrochloride ##STR00188## 178-179.degree.
U.S. Pat. No. 1,948,162 Corbasil, Cobefrin Function: Dermatitis
Herpetiformis Suppressant Dapsone ##STR00189## 175-176.degree.
Avlosulfon, Croysulfone, Diphenasone, Disulone, Dumitone, Eporal,
Novophone, Sulfona-Mae, Sulphadine, Udolac Sulfapyridine Sodium
Salt ##STR00190## 190-191.degree. U.S. Pat. No. 2,275,354
Izopiridina, Soludagenan Function: Diuretic Mercaptomerin Sodium
##STR00191## 150-155.degree. U.S. Pat. No. 2,576,349 Mercumatilin
Sodium ##STR00192## 155-160.degree. U.S. Pat. No. 2,667,442
Function: Dopamine Receptor Agonist Pergolid ##STR00193##
206-209.degree. U.S. Pat. No. 4,166,182 Pramipexole Dihydro-
chloride ##STR00194## 296-298.degree. U.S. Pat. No. 4,886,812
Mirapex, Mirapexin, Sifrol Function: Dopamine Receptor Antagonist
Amisulpride ##STR00195## 126-127.degree. U.S. Pat. No. 4,401,822
Sulpiride ##STR00196## 178-180.degree. U.S. Pat. No. 3,342,826
Alilit, Aiglonyl, Coolspan, Dobren, Dogmatil, Dogmatyl, Dolmatil,
Guastil, Meresa, Miradol, Mierbanil, Misulvan, Neogama, Omperan,
Pyrikappl, Sernevin, Splotin, Sulpitil, Sursumid, Trilan Function:
Emetic Cephaeline ##STR00197## 115-116.degree. Function:
Expectorant Bromhexine ##STR00198## 237-238.degree. BE 625022
Ambroxol Hydrochloride ##STR00199## 233-234.degree. U.S. Pat. No.
3,536,713 Abramen, Ambril, Bronchopront, Duramucal, Fluibron,
Fluixol, Frenopect, Lindoxyl, Motosol, Mucofar, Muscolvan,
Mucoclear, Mucovent, Pect, Solvolan, Stas- Hustenloser, Surbronc,
Surfactal Function: Gastric & Pancreatic Secretion Stimulant
Carnitine ##STR00200## U.S. Pat. Nos. 4,255,449 4,315,944 Function:
Gastroprokinetic Cinitapride ##STR00201## U.S. Pat. No. 5,026,858
Tartate, Cidine Cisapride ##STR00202## 109.8.degree. U.S. Pat. No.
4,962,115 Acenalin, Alimix, Cipril, Prepulsick, Propulside, Risamol
Function: Glucocorticoid Cortivazol ##STR00203## 160-165.degree.
U.S. Pat. No. 3,067,194/ U.S. Pat. No. 3,300,483 Enoxolone
##STR00204## 296.degree. GB 833184 Function: Gonad-Stimulating
Principle Clomiphene ##STR00205## 116-118.degree. U.S. Pat. No.
2,914,563 Citrate, Clomid, Clomphid, Clomricl, Clostilbeggt,
Dyneric, Ikaclomine, Pergotime, Serophene Function: Hemorheologic
Agent Pentoxifylline ##STR00206## 105.degree. U.S. Pat. No.
3,422,107 Oxpentifylline, Vasofirin, Azopentat, Dorapental,
Rentglin, Torental, Trental Function: Hemostatic Adrenalone
##STR00207## 235.degree. DE 152814 DE 277540 Adrenone, Stryphon
Carbazo- chrome Sodium Sulfonate ##STR00208## 227-228.degree. GB
795184 AC17, Adenaron, Adona, Carbazon, Donaseren, Emex, Odanon,
Tazin Function: Hepatoprotectant Thioctic Acid ##STR00209## U.S.
Pat. Nos. 2,980,716 3,049,549 3,223,712 Biletan, Thioctacid,
Thioctan, Tioctan Timonacid ##STR00210## FR 173184 Norgemen,
Thioproline, Detokepa, Hepalidine, Heparegen, Thiazolidin Function:
Immono modulator Pidotimod ##STR00211## 194-198.degree. U.S. Pat.
No. 4,839,387 Bucillamine 139-140.degree. U.S. Pat. No. 4,305,958
Rimatil Function: Immono suppressant 6-Mercapto- purine
##STR00212## 313-314.degree. U.S. Pat. Nos. 2,697,709 2,721,866
Leuberin, Mercaleubin Brequinar ##STR00213## 315-317.degree. U.S.
Pat. No. 4,680,299 Function: Keratolytic Retinoic Acid ##STR00214##
180-181.degree. U.S. Pat. No. 3,746,730 Aberd, Airol, Arite,
Eudgna, Kerlocal, Renova Salicylic Acid ##STR00215## 159.degree.
Acnisal, Duofilm, Duoplant, Keralyt, Occlusal, Verrugon Function:
Lexative/Cathartic Docusate Calcium (Sodium) ##STR00216## U.S. Pat.
Nos. 3,035,973 2,028,091 Sofale Picosolfate Sodium ##STR00217##
272-275.degree. U.S. Pat. Nos. 3,528,986 3,558,643 Guttalax-Fher,
Laxoberal, Laxoberon, Neopax, Pico-Salax Function: Leukotriene
Antagonist Ibudilast ##STR00218## 53-54.degree. U.S. Pat. No.
3,850,941 Ketas Zafirlukast ##STR00219## 138-140.degree. U.S. Pat.
No. 4,859,692 Accolate Function: Lipotropic Choline Chloride
##STR00220## U.S. Pat. No. 2,623,901 Biocolina, Hepacholine,
Lipotril Methionine ##STR00221## 280-282.degree. Acimethin
Function: Lupos Erythematosos Suppressant Bismuth Sodium
Triglycollamate ##STR00222## U.S. Pat. No. 2,348,984 Bistrimate
Chloroquine ##STR00223## 193-195.degree. U.S. Pat. No. 2,233,970
Aralen, Artriclin, Bemaphate, Capquin, Nivaquine B, Reamachlor,
Sanoquin Function: Matrix Metallo-proteinase Inhibitor Prinomastat
##STR00224## 149.8.degree. WO 97 20824 Function: Miotic Carbachol
##STR00225## 207.degree. U.S. Pat. No. 1,894,162 Doryl, Isopto
Carbachol, Zestryl, Miostat Neostigmine ##STR00226## 167.degree.
U.S. Pat. No. 1,905,990 Function: Mucolytic Acetylcysteine
##STR00227## 109-110.degree. U.S. Pat. No. 3,184,505 Bronac,
Fabrol, Fluimueil, Mocosil, Moeret Bromhexine ##STR00228##
237.5.degree. BE 625022 Function: Muscle Relaxant (Skeletal)
Tetrazepam ##STR00229## 144.degree. U.S. Pat. No. 3,426,014
Muscaril, Muokelat, Myolastan Tizanidine ##STR00230##
221-223.degree. U.S. Pat. No. 3,843,668 Function: Mydriatic
Tropicamide ##STR00231## 96-97.degree. U.S. Pat. No. 2,726,245
Mydriacyl, Mydriaticum Phenylephrine Hydrochloride ##STR00232##
140-145.degree. U.S. Pat. No. 1,932,347/ U.S. Pat. No. 1,954,389
Adrianol, Ak-Dilate, Alc-Nefrin, Isophirin, m-Sympatol, Neophryn
Function: Naroctic Antagonist Cyclazocine ##STR00233##
201-204.degree. BE 611000 Amiphenazole ##STR00234## 163-164.degree.
Dizol, Daptazole, Daptazile, Fenamizol Function: Neuraminidase
Inhibitor Zanamivir ##STR00235## 256.degree. WO 91 16320 Function:
Neuromuscular Blocking Agent Succinyl- choline Bromide/ Chloride/
Iodide ##STR00236## 156-163.degree. Fazadinium Bromide ##STR00237##
215.degree. U.S. Pat. No. 3,773,746 Fazadon Function: Neutral
Endopetidase Inhibitor Omapatrilat ##STR00238## 218-220.degree.
U.S. Pat. No. 5,508,272 Vauler Function: Neuroprotective Riluzole
##STR00239## 119.degree. U.S. Pat. No. 4,370,338 Rilutek
Repinotan ##STR00240## 192-194.degree. U.S. Pat. No. 5,137,901
Function: Nootropic Indeloxazine Hydrochloride ##STR00241## U.S.
Pat. No. 4,109,088 Elen, Noin Donepezil ##STR00242##
211-212.degree. U.S. Pat. No. 4,895,841 Aricept Function: Oxytocic
Carboprost ##STR00243## 55-56.degree. U.S. Pat. No. 3,728,382
Function: Potassium Channel Activator/Opener Pinacidil ##STR00244##
164-165.degree. U.S. Pat. No. 4,057,636 Pindac Nicorandil
##STR00245## 92-93.degree. U.S. Pat. No. 4,200,640 Adancor, Ikorel,
Perisalol, Sigmart Function: Potassium Channel Blocker Fampridine
##STR00246## 158-159.degree. Tedisamil ##STR00247## 195-197.degree.
U.S. Pat. No. 4,550,112 Function: Prolactin Inhibitor Cabergoline
##STR00248## 102.degree. U.S. Pat. No. 4,526,892 Cabaser, Dostinex
Function: Prostaglandin Beraprost ##STR00249## U.S. Pat. No.
4,479,802 Function: Respiratory Stimulant Dimefline ##STR00250##
213-214.degree. U.S. Pat. No. 3,147,258 Fominoben ##STR00251##
122-123.degree. U.S. Pat. No. 3,661,903 Function: Sclerosing Agent
2-Hexyl- decanoic Acid ##STR00252## 140-150.degree. Sodium
Tetradecyl Sulfate ##STR00253## Sotradecol, Tergitol Function:
Sedative/Hypnotic Flurazepam ##STR00254## 77-82.degree. U.S. Pat.
Nos. 3,299,053 3,567,710 Felmeme, Noctosom, Stacuroderm
Etodroxizine ##STR00255## liquid GB 8172321 Function:
Succinylcholine Synergist Hexafluorenium Bromide ##STR00256##
188-189.degree. U.S. Pat. No. 2,783,237 Mylexen Function: Tocolytic
Ritodrine ##STR00257## 88-90.degree. U.S. Pat. No. 3,410,944
Terbutaline ##STR00258## 119-122.degree. U.S. Pat. No. 3,937,838
Function: Ultraviolet Screen p-Amino- benzoic Acid ##STR00259##
187-187-5.degree. U.S. Pat. Nos. 2,878,282 2,947,781 2,735,865
Pabanol Solisobenzone ##STR00260## 145.degree. GB 1136525 Songard,
Uvinol Function: Uricosuric Ticrynafen ##STR00261## 148.degree.
U.S. Pat. No. 3,758,506 Orotic Acid ##STR00262## 345.degree. U.S.
Pat. Nos. 2,937,175 3,086,917 Oropor, Orotyl Function: Vasodilator
(Cerebral) Nafronyl ##STR00263## 190.degree. U.S. Pat. No.
3,334,096 Dubimax, Gevatran Nicametate ##STR00264## 155-157.degree.
Eucast Function: Vasodilator (Coronary) Perhexiline ##STR00265##
243-245.5.degree. GB 1025578 Cloricromen ##STR00266##
147-148.degree. U.S. Pat. No. 4,452,811 Function: Vasodilator
(Peripheral) Ciclonicate ##STR00267## 127-128.degree. DE 1910481
2406849 Cinepazide ##STR00268## 135.degree. U.S. Pat. No. 3,634,411
Function: Vasprotectant Chromocarb ##STR00269## 250-251.degree.
U.S. Pat. No. 3,816,470 Dobesilate Calcium ##STR00270##
>300.degree. U.S. Pat. No. 3,509,207 Function: Vitamin/Vitamin
Source Thiamine (Vit. B) ##STR00271## dec 248.degree. Pyridoxine
Hydrochloride (Vit. B.sub.5) ##STR00272## 205-212.degree. U.S. Pat.
Nos. 2,680,743 2,734,063 2,904,551 3,024,244 Function: Vulnerary
Oxaceptrol ##STR00273## 133-134.degree. U.S. Pat. Nos. 3,860,607
3,891,765 3,932,638 Acetylcysteine ##STR00274## 109-110.degree.
U.S. Pat. No. 3,184,505 Brunac, Fabrol, Fluimucil, Fluprowit,
Mucomgst, Mocosil, Tixair Function: Wilson's Disease Treatment
Penicillamine ##STR00275## 202-206.degree. Depen, Distamine,
Mercaptyl, Sofortan, Trolovol Function: Xanthine Oxidase Inhibitor
Allopurinol ##STR00276## >350.degree. U.S. Pat. Nos. 2,868,803
3,474,098 Adenoal, Aloral, Cosonic, Remid, Riball ##STR00277##
[0149] Further examples of pharmaceutical actives that are ionic or
can be made ionic and combined with other ions to form the
disclosed ionic liquid compositions are detailed below, along with
their typically pharmaceutical use.
[0150] Adrenergic: adrenalone, amidephrine mesylate, apracionidine
hydrochloride, brimonidine tartrate, dapiprazole hydrochloride,
deterenol hydrochloride, dipivefrin, dopamine hydrochloride,
ephedrine sulfate, epinephrine, epinephrine bitartrate, epinephryl
borate, esproquin hydrochloride, etafedrine hydrochloride,
hydroxyamphetamine hydrobromide, levonordefrin, mephentermine
sulfate, metaraminol bitartrate, metizoline hydrochloride,
naphazoline hydrochloride, norepinephrine bitartrate, oxidopamine,
oxymetazoline hydrochloride, phenylephrine hydrochloride,
phenylpropanolamine hydrochloride, phenylpropanolamine polistirex,
prenalterol hydrochloride, propylhexedrine, pseudoephedrine
hydrochloride, tetrahydrozoline hydrochloride, tramazoline
hydrochloride, xylometazoline hydrochloride.
[0151] Adrenocortical steroid: ciprocinonide, desoxycorticosterone
acetate, desoxycorticosterone pivalate, dexamethasone acetate,
fludrocortisone acetate, flumoxonide, hydrocortisone hemisuccinate,
methylprednisolone hemisuccinate, naflocort, procinonide,
timobesone acetate, tipredane.
[0152] Adrenocortical suppressant: aminogiutethimide,
trilostane.
[0153] Alcohol deterrent: disulfuram.
[0154] Aldosterone antagonist: canrenoate potassium, canrenone,
dicirenone, mexrenoate potassium, prorenoate potassium,
spironolactone.
[0155] Amino acid: alanine, aspaitic acid, cysteine hydrochloride,
cystine, histidine, isoleucine, leucine, lysine, lysine acetate,
lysine hydrochloride, methionine, phenylalanine, proline, serine,
threonine, tryptophan, tyrosine, valine.
[0156] Ammonia detoxicant: arginine: arginine glutamate, arginine
hydrochloride.
[0157] Anabolic: bolandiol dipropionate, bolasterone, boldenone
undecylenate, bolenol, bolnantalate, ethylestrenol, methenolone
acetate, methenolone enanthate, mibolerone, nandrolone cyclotate,
norbolethone, quinbolone, stenbolone acetate, tibolone,
zeranol.
[0158] Analeptic: modafinil.
[0159] Analgesic: acetaminophen, alfentanil hydrochloride,
aminobenzoate potassium, aminobenzoate sodium, anidoxime,
anileridine, anileridine hydrochloride, anilopam hydrochloride,
anirolac, antipyrine, aspirin, benoxaprofen, benzydamine
hydrochloride, bicifadine hydrochloride, brifentanil hydrochloride,
bromadoline maleate, bromfenac sodium, buprenorphine hydrochloride,
butacetin, butixirate, butorphanol, butorphanol tartrate,
carbamazepine, carbaspirin calcium, carbiphene hydrochloride,
carfentanil citrate, ciprefadol succinate, ciramadol, ciramadol
hydrochloride, clonixeril, clonixin, codeine, codeine phosphate,
codeine sulfate, conorphone hydrochloride, cyclazocine, dexoxadrol
hydrochloride, dexpemedolac, dezocine, diflunisal, dihydrocodeine
bitartrate, dimefadane, dipyrone, doxpicomine hydrochloride,
drinidene, enadoline hydrochloride, epirizole, ergotamine tartrate,
ethoxazene hydrochloride, etofenamate, eugenol, fenoprofen,
fenoprofen calcium, fentanyl citrate, floctafenine, flufenisal,
flunixin, flunixin meglumine, flupirtine maleate, fluproquazone,
fluradoline hydrochloride, flurbiprofen, hydromorphone
hydrochloride, ibufenac, indoprofen, ketazocine, ketorfanol,
ketorolac tromethamine, letimide hydrochloride, levomethadyl
acetate, levomethadyl acetate hydrochloride, levonantradol
hydrochloride, levorphanol tartrate, lofemizole hydrochloride,
lofentanil oxalate, lorcinadol, lomoxicam, magnesium salicylate,
mefenamic acid, menabitan hydrochloride, meperidine hydrochloride,
meptazinol hydrochloride, methadone hydrochloride, methadyl
acetate, methopholine, methotrimeprazine, metkephamid acetate,
mimbane hydrochloride, mirfentanil hydrochloride, molinazone,
morphine sulfate, moxazocine, nabitan hydrochloride, nalbuphine
hydrochloride, nalmexone hydrochloride, namoxyrate, nantradol
hydrochloride, naproxen, naproxen sodium, naproxol, nefopam
hydrochloride, nexeridine hydrochloride, noracymethadol
hydrochloride, ocfentanil hydrochloride, octazamide, olvanil,
oxetorone fumarate, oxycodone, oxycodone hydrochloride, oxycodone
terephthalate, oxymorphone hydrochloride, pemedolac, pentamorphone,
pentazocine, pentazocine hydrochloride, pentazocine lactate,
phenazopyridine hydrochloride, phenyramidol hydrochloride,
picenadol hydrochloride, pinadoline, pirfenidone, piroxicam
olamine, pravadoline maleate, prodilidine hydrochloride, profadol
hydrochloride, propiram fumarate, propoxyphene hydrochloride,
propoxyphene napsylate, proxazole, proxazole citrate, proxorphan
tartrate, pyrroliphene hydrochloride, remifentanil hydrochloride,
salcolex, salethamide maleate, salicylamide, salicylate meglumine,
salsalate, sodium salicylate, spiradoline mesylate, sufentanil,
sufentanil citrate, talmetacin, talniflumate, talosalate,
tazadolene succinate, tebufelone, tetrydamine, tifurac sodium,
tilidine hydrochloride, tiopinac, tonazocine mesylate, tramadol
hydrochloride, trefentanil hydrochloride, trolamine, veradoline
hydrochloride, verilopam hydrochloride, volazocine, xorphanol
mesylate, xylazine hydrochloride, zenazocine mesylate, zomepirac
sodium, zucapsaicin.
[0160] Androgen: fluoxymesterone, mesterolone, methyltestosterone,
nandrolone decanoate, nandrolone phenpropionate, nisterime acetate,
oxandrolone, oxymetholone, silandrone, stanozolol, testosterone,
testosterone cypionate, testosterone enanthate, testosterone
ketolaurate, testosterone phenylacetate, testosterone propionate,
trestolone acetate.
[0161] Anesthesia, adjunct to: sodium oxybate.
[0162] Anesthetic: aliflurane, benoxinate hydrochloride,
benzocaine, biphenamine hydrochloride, bupivacaine hydrochloride,
butamben, butamben picrate, chloroprocaine hydrochloride, cocaine,
cocaine hydrochloride, cyclopropane, desflurane, dexivacaine,
diamocaine cyclamate, dibucaine, dibucaine hydrochloride, dyclonine
hydrochloride, enflurane, ether, ethyl chloride, etidocaine,
etoxadrol hydrochloride, euprocin hydrochloride, fluoroxene,
halothane, isobutamben, isoflurane, ketamine hydrochloride,
levoxadrol hydrochloride, lidocaine, lidocaine hydrochloride,
mepivacaine hydrochloride, methohexital sodium, methoxyflurane,
midazolam hydrochloride, midazolam maleate, minaxolone, nitrous
oxide, norflurane, octodrine, oxethazaine, phencyclidine
hydrochloride, pramoxine hydrochloride, prilocaine hydrochloride,
procaine hydrochloride, propanidid, proparacaine hydrochloride,
propofol, propoxycaine hydrochloride, pyrrocaine, risocaine,
rodocaine, roflurane, salicyl alcohol, sevoflurane, tellurane,
tetracaine, tetracaine hydrochloride, thiamylal, thiamylal sodium,
thiopental sodium, tiletamine hydrochloride, zolamine
hydrochloride.
[0163] Anorectic compounds including dexfenfluramine.
[0164] Anorexic: aminorex, amphecloral, chlorphentermine
hydrochloride, clominorex, clortermine hydrochloride,
diethylpropion hydrochloride, fenfluramine hydrochloride,
fenisorex, fludorex, fluminorex, levamfetamine succinate, mazindol,
mefenorex hydrochloride, phenmetrazine hydrochloride, phentermine,
sibutramine hydrochloride.
[0165] Antagonist: atipamezole, atosiban, bosentan, cimetidine,
cimetidine hydrochloride, clentiazem maleate, detirelix acetate,
devazepide, donetidine, etintidine hydrochloride, famotidine,
fenmetozole hydrochloride, flurnazenil, icatibant acetate,
icotidine, isradipine, metiarnide, nadide, nalmefene, nalmexone
hydrochloride, naloxone hydrochloride, naltrexone, nilvadipine,
oxilorphan, oxmetidine hydrochloride, oxmetidine mesylate,
quadazocine mesylate, ranitidine, ranitidine bismuth citrate,
ranitidine hydrochloride, sufotidine, teludipine hydrochloride,
tiapamil hydrochloride, tiotidine, vapiprost hydrochloride,
zaltidine hydrochloride.
[0166] Anterior pituitary activator: epimestrol.
[0167] Anterior pituitary suppressant: danazol.
[0168] Anthelmintic; albendazole, anthelmycin, bromoxanide,
bunamidine hydrochloride, butonate, cambendazole, carbantel lauryl
sulfate, clioxanide, closantel, cyclobendazole, dichlorvos,
diethylcarbamazine citrate, dribendazole, dymanthine hydrochloride,
etibendazole, fenbendazole, furodazole, hexylresorcinol,
mebendazole, morantel tartrate, niclosamide, nitramisole
hydrochloride, nitrodan, oxantel pamoate, oxfendazole,
oxibendazole, parbendazole, piperamide maleate, piperazine,
piperazine citrate, piperazine edetate calcium, proclonol, pyrantel
pamoate, pyrantel tartrate, pyrvinium pamoate, rafoxanide,
stilbazium tetramisole hydrochloride, thiabendazole, ticarbodine,
tioxidazole, triclofenol piperazine, vincofos, zilantel.
[0169] Anti-acne: adapalene, erythromycin salnacedin, inocoterone
acetate, accutane.
[0170] Anti-adrenergic: acebutolol, alprenolol hydrochloride,
atenolol, bretylium tosylate, bunolol hydrochloride, carteolol
hydrochloride, celiprolol hydrochloride, cetamolol hydrochloride,
cicloprolol hydrochloride, dexpropranolol hydrochloride, diacetolol
hydrochloride, dihydroergotamine mesylate, dilevalol hydrochloride,
esmolol hydrochloride, exaprolol hydrochloride, fenspiride
hydrochloride, flestolol sulfate, labetalol hydrochloride,
levobetaxolol hydrochloride, levobunolol hydrochloride, metalol
hydrochloride, metoprolol, metoprolol tartrate, nadolol, pamatolol
sulfate, penbutolol sulfate, phentolamine mesylate, practolol,
propranolol hydrochloride, proroxan hydrochloride, solypertine
taitrate, sotalol hydrochloride, timolol, maleate, tiprenolol
hydrochloride, tolamolol, zolertine hydrochloride.
[0171] Anti-allergic: amlexanox, astemizole, azelastine
hydrochloride, ectazolast, minocromil, nedocromil, nedocromil
calcium, nedocromil sodium, nivimedone sodium, pemirolast
potassium, pentigetide, pirquinozol, poisonoak extract, probicromil
calcium, proxicromil, repirinast, tetrazolast meglumine,
thiazinamium chloride, tiacrilast, tiacrilast sodium, tiprinast
meglumine, tixanox.
[0172] Anti-amebic: berythromycin, bialamicol hydrochloride,
chloroquine, chloroquine hydrochloride, chloroquine phosphate,
clamoxyquin hydrochloride, clioquinol, emetine hydrochloride,
iodoquinol, paromomycin sulfate, quinfamide, symetine
hydrochloride, teclozan, tetracycline, tetracycline
hydrochloride.
[0173] anti-androgen: benorterone, cioteronel, cyproterone acetate,
delmadinone acetate, oxendolone, topterone, zanoterone.
[0174] Anti-anemic: epoetin alfa, epoetin beta, ferrous sulfate,
dried, leucovorin calcium.
[0175] Anti-anginal: amlodipine besylate, amlodipine maleate,
betaxolol hydrochloride, bevantolol hydrochloride, butoprozine
hydrochloride, carvedilol, cinepazet maleate, metoprolol succinate,
molsidomine, monatepil maleate, primidolol, ranolazine
hydrochloride, tosifen, verapamil hydrochloride.
[0176] Anti-anxiety agent: adatanserin hydrochloride, alpidem,
binospirone mesylate, bretazenil, glemanserin, ipsapirone
hydrochloride, maleate, ocinaplon, ondansetron hydrochloride,
panadiplon, pancopride, pazinaclone, serazapine hydrochloride,
tandospirone citrate, zalospirone hydrochloride.
[0177] Anti-arthritic: lodelaben.
[0178] Anti-asthmatic: ablukast, ablukast sodium, azelastine
hydrochloride, bunaprolast, cinalukast, crornitrile sodium,
cromolyn sodium, enofelast, isamoxole, ketotifen fumarate,
levcromakalim, lodoxamide ethyl, lodoxamide tromethamine,
montelukast sodium, ontazolast, oxarbazole, oxatomide, piriprost,
piriprost potassium, pirolate, pobilukast edamine, quazolast,
repirinast, ritolukast, sulukast, tetrazolast meglumine, tiaramide
hydrochloride, tibenelast sodium, tomelukast, tranilast, verlukast,
verofylline, zarirlukast.
[0179] Anti-atherosclerotic: mifobate, timefurone.
[0180] Anticholelithic: monoctanoin.
[0181] Anticholelithogenic: chenodiol, ursodiol.
[0182] Anticholinergic: alverine citrate, anisotropine
methylbromide, atropine, atropine oxide hydrochloride, atropine
sulfate, belladonna, benapryzine hydrochloride, benzetimide
hydrochloride, benzilonium bromide, biperiden, biperiden
hydrochloride, biperiden lactate, clidinium bromide, cyclopentolate
hydrochloride, dexetimide, dicyclomine hydrochloride, dihexyverine
hydrochloride, domazoline famarate, elantrine, elucaine,
ethybenztropine, eucatropine hydrochloride, glycopyrrolate,
heteronium bromide, homatropine hydrobromide, homatropine
methylbromide, hyoscyamine, hyoscyamine hydrobromide, hyoscyamine
sulfate, isopropamide iodido, mepenzolate bromide, methylatropine
nitrate, metoquizine, oxybutynin chloride, parapenzolate bromide,
pentapiperium methylsulfate, phencarbamide, poldine methylsulfate,
proglumide, propantheline bromide, propenzolate hydrochloride,
scopolamine hydrobromide, tematropium methylsulfate, tiquinamide
hydrochloride, tofenacin hydrochloride, toquizine, triampyzine
sulfate, trihexyphenidyl hydrochloride, tropicamide.
[0183] Anticoagulant: ancrod, anticoagulant citrate dextrose
solution, anticoagulant citrate phosphate dextrose adenine
solution, anticoagulant citrate phosphate dextrose solution,
anticoagulant heparin solution, anticoagulant sodium citrate
solution, ardeparin sodium, bivalirudin, bromindione, dalteparin
sodium, desirudin, dicumnarol, heparin calcium, heparin sodium,
lyapolate sodium, nafamostat mesylate, phenprocoumon, tinzaparin
sodium, warfarin sodium.
[0184] Anticoccidal: maduramicin.
[0185] Anticonvulsant: albutoin, ameltolide, atolide, buramate,
carbamazepine, cinromide, citenamide, clonazepam, cyheptamide,
dezinamide, dimethadione, divalproex sodium, eterobarb,
ethosuximide, ethotoin, flurazepam hydrochloride, fluzinamide,
fosphenytoin sodium, gabapentin, ilepcimide, lamotrigine, magnesium
sulfate, mephenyloin, mephobarbital, methetoin, methsuximide,
milacemide hydrochloride, nabazenil, nafimidone hydrochloride,
nitrazepam, phenacemide, phenobarbital, phenobarbital sodium,
phensuximide, phenyloin, phenyloin sodium, primidone, progabide,
ralitoline, remacemide hydrochloride, ropizine, sabeluzole,
stiripentol, sulthiame, thiopental sodium, tiletamine
hydrochloride, topiramate, trimethadione, valproate sodium,
valproic acid, vigabatrin, zoniclezole hydrochloride,
zonisamide.
[0186] Antidepressant: adatanserin hydrochloride, adinazolam,
adinazolam mesylate, alaproclate, aletamine hydrochloride, amedalin
hydrochloride, amitriptyline hydrochloride, amoxapine, aptazapine
maleate, azaloxan fumarate, azepindole, azipramine hydrochloride,
bipenamol hydrochloride, bupropion hydrochloride, butacetin,
butriptyline hydrochloride, caroxazone, cartazolate, ciclazindol,
cidoxepin hydrochloride, cilobamine mesylate, clodazon
hydrochloride, clomipramine hydrochloride, cotinine famarate,
cyclindole, cypenamine hydrochloride, cyprolidol hydrochloride,
cyproximide, daledalin tosylate, dapoxetine hydrochloride, dazadrol
maleate, dazepinil hydrochloride, desipramine hydrochloride,
dexamisole, deximafen, dibenzepin hydrochloride, dioxadrol
hydrochloride, dothiepin hydrochloride, doxepin hydrochloride,
duloxetine hydrochloride, eclanamine maleate, encyprate,
etoperidone hydrochloride, fantridone hydrochloride, fehmetozole
hydrochloride, fenmetramide, fezolamine fumarate, fluotracen
hydrochloride, fluoxetine, fluoxetine hydrochloride, fluparoxan
hydrochloride, gamfexine, guanoxyfen sulfate, imafen hydrochloride,
imiloxan hydrochloride, imipramine hydrochloride, indeloxazine
hydrochloride, intriptyline hydrochloride, iprindole,
isocarboxazid, ketipramine fumarate, lofepramine hydrochloride,
lortalamine, maprotiline, maprotiline hydrochloride, melitracen
hydrochloride, milacemide hydrochloride, minaprine hydrochloride,
mirtazapine, moclobemide, modaline sulfate, napactadine
hydrochloride, napamezole hydrochloride, nefazodone hydrochloride,
nisoxetine, nitrafudam hydrochloride, nomifensine maleate,
nortriptyline hydrochloride, octriptyline phosphate, opipramol
hydrochloride, oxaprotiline hydrochloride, oxypertine, paroxetine,
phenelzine sulfate, pirandamine hydrochloride, pizotyline,
pridefine hydrochloride, prolintane hydrochloride, protriptyline
hydrochloride, quipazine maleate, rolicyprine, seproxetine
hydrochloride, sertraline hydrochloride, sibutramine hydrochloride,
sulpiride, suritozole, tametraline hydrochloride, tampramine
fumarate, tandamine hydrochloride, thiazesim hydrochloride,
thozalinone, tomoxetine hydrochloride, trazodone hydrochloride,
trebenzomine hydrochloride, trimipramine, trimipramine maleate,
venlafaxine hydrochloride, viloxazine hydrochloride, zimeldine
hydrochloride, zometapine.
[0187] Antidiabetic: acetohexamide, buformin, butoxamine
hydrochloride, camiglibose, chlorpropamide, ciglitazone,
englitazone sodium, etoformin hydrochloride, gliamilide,
glibornuride, glicetanile sodium, glifiumide, glipizide, glucagon,
glyburide, glyhexamide, glymidine sodium, glyoctamide, glyparamide,
insulin, insulin, dalanated, insulin human, insulin human,
isophane, insulin human zinc, insulin human zinc, extended,
insulin, isophane, insulin lispro, insulin, neutral, insulin zinc,
insulin zinc, extended, insulin zinc, prompt, linogliride,
linogliride fumarate, metformin, methyl palmoxirate, palmoxirate
sodium, pioglitazone hydrochloride, pirogliride tartrate,
proinsulin human, seglitide acetate, tolazamide, tolbutamide,
tolpyrramide, troglitazone, zopolrestat, and sitagliptin.
[0188] Antidiarrheal: rolgamidine, diphenoxylate hydrochloride
(lomotil), metronidazole (flagyl), methylprednisolone (medrol),
sulfasalazine (azulfidine).
[0189] Antidiuretic: argipressin tannate, desmopressin acetate,
lypressin.
[0190] Antidote: dimercaprol, edrophonium chloride, fomepizole,
leucovorin calcium, levoleucovorin calcium, methylene blue,
prolamine sulfate.
[0191] Antidyskinetic: selegiline hydrochloride.
[0192] Anti-emetic: alosetron hydrochloride, batanopride
hydrochloride, bemesetron, benzquinamide, chlorpromazine,
chlorpromazine hydrochloride, clebopride, cyclizine hydrochloride,
dimenhydrinate, diphenidol, diphenidol hydrochloride, diphenidol
pamoate, dolasetron mesylate, domperidone, dronabinol, fludorex,
flumeridone, galdansetron hydrochloride, granisetron, granisetron
hydrochloride, lurosetron mesylate, meclizine hydrochloride,
metoclopramide hydrochloride, metopimazine, ondansetron
hydrochloride, pancopride, prochlorperazine, prochlorperazine
edisylate, prochlorperazine maleate, promethazine hydrochloride,
thiethylperazine, thiethylperazine malate, thiethylperazine
maleate, trimethobenzamide hydrochloride, zacopride
hydrochloride.
[0193] Anti-epileptic: felbamate, loreclezole, tolgabide.
[0194] Anti-estrogen: clometherone, delmadinone acetate, nafoxidine
hydrochloride, nitromifene citrate, raloxifene hydrochloride,
tamoxifen citrate, toremifene citrate, trioxifene mesylate.
[0195] Antifibrinolytic: nafamostat mesylate.
[0196] Antifungal: acrisorcin, ambruticin, amphotericin b,
azaconazole, azaserine, basifungin, bifonazole, biphenamine
hydrochloride, bispyrithione magsulfex, butoconazole nitrate,
calcium undecylenate, candicidin, carbol-fuchsin, chlordantoin,
ciclopirox, ciclopirox olamine, cilofungin, cisconazole,
clotrimazole, cuprimyxin, denofungin, dipyrithione, doconazole,
econazole, econazole nitrate, enilconazole, ethonam nitrate,
fenticonazole nitrate, filipin, fluconazole, flucytosine,
fungimycin, griseofulvin, hamycin, isoconazole, itraconazole,
kalafungin, ketoconazole, lomofimgin, lydimycin, mepartricin,
miconazole, miconazole nitrate, monensin, monensin sodium,
naftifine hydrochloride, neomycin undecylenate, nifuratel,
nifurmerone, nitralamine hydrochloride, nystatin, octanoic acid,
orconazole nitrate, oxiconazole nitrate, oxifungin hydrochloride,
parconazole hydrochloride, partricin, potassium iodide, proclonol,
pyrithione zinc, pyrrolnitrin, rutamycin, sanguinarium chloride,
saperconazole, scopafungin, selenium sulfide, sinefungin,
sulconazole nitrate, terbinafine, terconazole, thiram, ticlatone,
tioconazole, tolciclate, tolindate, tolnaftate, triacetin,
triafungin, undecylenic acid, viridofulvin, zinc undecylenate,
zinoconazole hydrochloride. One specific antifungal that is
suitable is itraconazole.
[0197] Antiglaucoma agent: alprenoxime hydrochloride, colforsin,
dapiprazole hydrochloride, dipivefrin hydrochloride, naboctate
hydrochloride, pilocarpine, pimabine.
[0198] Antihemophilic: antihemophilic factor.
[0199] Antihemorrhagic: poliglusam.
[0200] Antihistaminic: acrivastine, antazoline phosphate,
astemizole, azatadine maleate, barmastine, bromodiphenhydramine
hydrochloride, brompheniramine maleate, carbinoxamine maleate,
cetirizine hydrochloride, chlorpheniramine maleate,
chlorpheniramine polistirex, cinnarizine, clemastine, clemastine
fumarate, closiramine aceturate, cycliramine maleate, cyclizine,
cyproheptadine hydrochloride, dexbrompheniramine maleate,
dexchlorpheniramine maleate, dimethindene maleate, diphenhydramine
citrate, diphenhydramine hydrochloride, dorastine hydrochloride,
doxylamine succinate, ebastine, levocabastine hydrochloride,
loratadine, mianserin hydrochloride, noberastine, orphenadrine
citrate, pyrabrom, pyrilamine maleate, pyroxamnine maleate,
rocastine hydrochloride, rotoxamine, tazifylline hydrochloride,
temelastine, terfenadine, tripelennamine citrate, tripelennamine
hydrochloride, triprolidine hydrochloride, zolamine
hydrochloride.
[0201] Antihyperlipidemic: cholestyramine resin, clofibrate,
colestipol hydrochloride, crilvastatin, dalvastatin,
dextrothyroxine sodium, fluvastatin sodium, gemfibrozil,
lecimibide, lovastatin, niacin, pravastatin sodium, probucol,
simvastatin, tiqueside, xenbucin.
[0202] Antihyperlipoproteinemic: acifran, beloxamide, bezafibrate,
boxidine, butoxamine hydrochloride, cetaben sodium, ciprofibrate,
gemcadiol, halofenate, lifibrate, meglutol, nafenopin, pimetine
hydrochloride, theofibrate, tibric acid, treloxinate.
[0203] Antihypertensive: alfazosin hydrochloride, alipamide,
althiazide, amiquinsin hydrochloride, amiodipine besylate,
amiodipine maleate, anaritide acetate, atiprosin maleate,
belfosdil, bemitradine, bendacalol mesylate, bendroflumethiazide,
benzthiazide, betaxolol hydrochloride, bethanidine sulfate,
bevantolol hydrochloride, biclodil hydrochloride, bisoprolol,
bisoprolol fumarate, bucindolol hydrochloride, bupicomide,
buthiazide, candoxatril, candoxatrilat, captopril, carvedilol,
ceronapril, chlorothiazide sodium, cicletanine, cilazapril,
clonidine, clonidine hydrochloride, clopamide, cyclopenthiazide,
cyclothiazide, darodipine, debrisoquin sulfate, delapril
hydrochloride, diapamide, diazoxide, dilevalol hydrochloride,
diltiazem malate, ditekiren, doxazosin mesylate, ecadotril,
enalapril maleate, enalaprilat, enalkiren, endralazine mesylate,
epithiazide, eprosartan, eprosartan mesylate, fenoldopam mesylate,
flavodilol maleate, flordipine, flosequinan, fosinopril sodium,
fosinoprilat, guanabenz, guanabenz acetate, guanacline sulfate,
guanadrel sulfate, guancydine, guanethidine monosulfate,
guanethidine sulfate, guanfacine hydrochloride, guanisoquin
sulfate, guanoclor sulfate, guanoctine hydrochloride, guanoxabenz,
guanoxan sulfate, guanoxyfen sulfate, hydralazine hydrochloride,
hydralazine polistirex, hydroflumethiazide, indacrinone,
indapamide, indolaprif hydrochloride, indoramin, indoramin
hydrochloride, indorenate hydrochloride, lacidipine, leniquinsin,
levcromakalim, lisinopril, lofexidine hydrochloride, losartan
potassium, losulazine hydrochloride, mebutamate, mecamylamine
hydrochloride, medroxalol, medroxalol hydrochloride,
methalthiazide, methyclothiazide, methyldopa, methyldopate
hydrochloride, metipranolol, metolazone, metoprolol fumarate,
metoprolol succinate, metyrosine, minoxidil, monatepil maleate,
muzolimine, nebivolol, nitrendipine, ofornine, pargyline
hydrochloride, pazoxide, pelanserin hydrochloride, perindopril
erbumine, phenoxybenzamine hydrochloride, pinacidil, pivopril,
polythiazide, prazosin hydrochloride, primidolol, prizidilol
hydrochloride, quinapril hydrochloride, quinaprilat, quinazosin
hydrochloride, quinelorane hydrochloride, quinpirole hydrochloride,
quinuclium bromide, ramipril, rauwolfia serpentina, reserpine,
saprisartan potassium, saralasin acetate, sodium nitroprusside,
sulfinalol hydrochloride, tasosartan, teludipine hydrochloride,
temocapril hydrochloride, terazosin hydrochloride, terlakiren,
tiamenidine, tiamenidine hydrochloride, ticrynafen, tinabinol,
tiodazosin, tipentosin hydrochloride, trichlormethiazide,
trimazosin hydrochloride, trimethaphan camsylate, trimoxamine
hydrochloride, tripamide, xipamide, zankiren hydrochloride,
zofenoprilat arginine.
[0204] Antihypotensive: ciclafrine hydrochloride, midodrine
hydrochloride.
[0205] Anti-infective: difioxacin hydrochloride, lauryl
isoquinolinium bromide, moxalactam disodium, ornidazole,
pentisomicin, sarafloxacin hydrochloride, protease inhibitors of
hiv and other retroviruses, integrase inhibitors of hiv and other
retroviruses, cefaclor (CECLOR.TM.), acyclovir (ZOVIRAX.TM.),
norfloxacin (NOROXIN.TM.), cefoxitin (MEFOXIN.TM.), cefuroxime
axetil (CEFTIN.TM.), ciprofloxacin (CIPRO.TM.).
[0206] Anti-infective, topical: alcohol, aminacrine hydrochloride,
benzethonium chloride: bithionolate sodium, bromchlorenone,
carbamide peroxide, cetalkonium chloride, cetylpyridinium chloride:
chlorhexidine hydrochloride, clioquinol, domiphen bromide,
fenticlor, fludazonium chloride, fuchsin, basic, furazolidone,
gentian violet, halquinols, hexachlorophene: hydrogen peroxide,
ichthammol, imidecyl iodine, isopropyl alcohol, mafenide acetate,
meralein sodium, mercufenol chloride, mercury; ammoniated,
methylbenzethonium chloride, nitrofurazone, nitromersol, octenidine
hydrochloride, oxychlorosene, oxychlorosene sodium,
parachlorophenol, camphorated, potassium permanganate,
povidone-iodine, sepazonium chloride, silver nitrate, sulfadiazine,
silver, symclosene, thimerfonate sodium, thimerosal: troclosene
potassium.
[0207] Anti-inflammatory: acetominophen, alclofenac, alclometasone
dipropionate, algestone acetonide, alpha amylase, amcinafal,
amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra,
anirolac, anitrazafen, apazone, balsalazide disodium, bendazac,
benoxaprofen, benzydamine hydrochloride, bromelains, broperamole,
budesonide, carprofen, cicloprofen, cintazone, cliprofen,
clobetasol propionate, clobetasone butyrate, clopirac, cloticasone
propionate, cormethasone acetate, cortodoxone, deflazacort,
desonide, desoximetasone, dexamethasone dipropionate, diclofenac
potassium, diclofenac sodium, diflorasone diacetate, diflumidone
sodium, diflunisal, difluprednate, diftalone, dimethyl sulfoxide,
drocinonide, endrysone, enlimomab, enolicam sodium, epirizole,
etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac,
fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort,
flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin
megiumine, fluocortin butyl, fluorometholone acetate, fluquazone,
fluthiprofen, fluretofen, fluticasone propionate, furaprofen,
furobufen, halcinonide, halobetasol propionate, halopredone
acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen
piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen,
indoxole, intrazole, isoflupredone acetate, isoxepac, isoxicam,
ketoprofen, lofemizole hydrochloride, lomoxicam, loteprednol
etabonate, meclofenamate sodium, meclofenamic acid, meclorisone
dibutyrate, mefenamic acid, mesalamine, meseclazone,
methylprednisolone suleptanate, momiflumate, nabumetone, naproxen,
naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein,
orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride,
pentosan polysulfate sodium, phenbutazone sodium glycerate,
pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine,
pirprofen, prednazate, prifelone, prodolic acid, proquazone,
proxazole, proxazole citrate, rimexolone, romazarit, salcolex,
salnacedin, salsalate, sangainarium chloride, seclazone,
sermetacin, sudoxicam, sulindac, suprofen, talmetacin,
talniflumate, talosalate, tebufelone, tenidap, tenidap sodium,
tenoxicam, tesicam, tesimide, tetrydamine, tiopinac, tixocortol
pivalate, tolmetin, tolmetin sodium, triclonide, triflumidate,
zidometacin, zomepirac sodium.
[0208] Antikeratinizing agent: doretinel, linarotene, pelretin.
[0209] Antimalarial: acedapsone, amodiaquine hydrochloride,
amquinate, arteflene, chloroquine, chloroquine hydrochloride,
chloroquine phosphate, cycloguanil pamoate, enpiroline phosphate,
hatofantrine hydrochloride, hydroxychloroquine sulfate, mefloquine
hydrochloride, menoctone, mirincamycin hydrochloride, primaquine
phosphate, pyrimethamine, quinine sulfate, tebuquine.
[0210] Antimicrobial: aztreonam, chlorhexidine gluconate, imidurea,
lycetamine, nibroxane, pirazmonam sodium, propionic acid,
pyrithione sodium, sanguinarium chloride, tigemonam dicholine.
[0211] Antimigraine: dolasetron mesylate, naratriptan
hydrochloride, sergolexole sumatriptan succinate, zatosetron
maleate.
[0212] Antimitotic: podofilox.
[0213] Antimycotic: amorolfine.
[0214] Antinauseant: buclizine hydrochloride, cyclizine lactate,
naboctate hydrochloride.
[0215] Antineoplastic: acivicin, aclarabicin, acodazole
hydrochloride, acrqnine, adozelesin, aldesleukin, altretamine,
ambomycin, ametantrone acetate, aminoglutethimide, amsacrine,
anastrozole, anthramycin, asparaginase, asperlin, azacitidine,
azetepa, azotomycin, batimastat, benzodepa, bicalutamide,
bisantrene hydrochloride, bisnafide dimesylate, bizelesin,
bleomycin sulfate, brequinar sodium, bropirimine, busulfan,
cactinomycin, calusterone, caracemide, carbetimer, carboplatin,
carmustine, carubicin hydrochloride, carzelesin, cedefingol,
chlorambucil, cirolemycin, cisplatin, cladribine, crisnatol
mesylate, cyclophosphamide, cytarabine, dacarbazine, dactinomycin,
daunorubicin hydrochloride, decitabine, dexormaplatin, dezaguanine,
dezaguanine mesylate, diaziquone, docetaxel, doxorubicin,
doxorubicin hydrochloride, droloxifene, droloxifene citrate,
dromostanolone propionate, duazomycin, edatrexate, eflomithine
hydrochloride, elsamitrucin, enloplatin, enpromate, epipropidine,
epirabicin hydrochloride, erbulozole, esorubicin hydrochloride,
estramustine, estramustine phosphate sodium, etanidazole,
ethiodized oil I 131, etoposide, etoposide phosphate, etoprine,
fadrozole hydrochloride, fazarabine, fenretinide, floxuridine,
fludarabine phosphate, fluorouracil, fluorocitabine, fosquidone,
fostriecin sodium, gemcitabine, gemcitabine hydrochloride, gold au
198, hydroxyurea, idarubicin hydrochloride, ifosfamide, ilmofosine,
interferon alfa-2a, interferon alfa-2b, interferon alfa-N1,
interferon alfa-N3, interferon beta-Ia, interferon gamma-Ib,
iproplatin, irinotecan hydrochloride, lanreotide acetate,
letrozole, leuprolide acetate, liarozole hydrochloride, lometrexol
sodium, lomustine, losoxantrone hydrochloride, masoprocol,
maytansine, mechlorethamine hydrochloride, megestrol acetate,
melengestrol acetate, melphalan, menogaril, mercaptopurine,
methotrexate, methotrexate sodium, metoprine, meturedepa,
mitindomide, mitocarcin, mitocromin, mitogillin, mitomalcin,
mitomycin, mitosper, mitotane, mitoxantrone hydrochloride,
mycophenolic acid, nocodazole, nogalamycin, ormaplatin, oxisuran,
paclitaxel, pegaspargase, peliomycin, pentamustine, peplomycin
sulfate, perfosfamide, pipobroman, piposulfan, piroxantrone
hydrochloride, plicamycin, plomestane, porfimer sodium,
porfiromycin, prednimustine, procarbazine hydrochloride, puromycin,
puromycin hydrochloride, pyrazofurin, riboprine, rogletimide,
safmgol, safingol hydrochloride, semustine, simtrazene, sparfosate
sodium, sparsomycin, spirogermanium hydrochloride, spiromustine,
spiroplatin, streptonigrin, streptozocin, strontium chloride sr 89,
sulofenur, talisomycin, taxane, taxoid, tecogalan sodium, tegafur,
teloxantrone hydrochloride, temoporfin, teniposide, teroxirone,
testolactone, thiamiprine, thioguanine, thiotepa, tiazofurin,
tirapazamine, topotecan hydrochloride, toremifene citrate,
trestolone acetate, triciribine phosphate, trimetrexate,
trimetrexate glucuronate, triptorelin, tubulozole hydrochloride,
uracil mustard, uredepa, vapreotide, verteporfin, vinblastine
sulfate, vincristine sulfate, vindesine, vindesine sulfate,
vinepidine sulfate, vinglycinate sulfate, vinleurosine sulfate,
vinorelbine tartrate, vinrosidine sulfate, vinzolidine sulfate,
vorozole, zeniplatin, zinostatin, zorubicin hydrochloride.
[0216] Other anti-neoplastic compounds include: 20-epi-1,25
dihydroxyvitamin D3, 5-ethynyluracil, abiraterone, aclarubicin,
acylfulvene, adecypenol, adozelesin, aldesleukin, ALL-TK
antagonists, altretamine, ambamustine, amidox, amifostine,
aminolevulinic acid, amrubicin, atrsacrine, anagrelide,
anastrozole, andrographolide, angiogenesis inhibitors, antagonist
D, antagonist G, antarelix, anti-dorsalizing morphogenetic
protein-1, antiandrogen, prostatic carcinoma, antiestrogen,
antineoplaston, antisense oligonucleotides, aphidicolin glycinate,
apoptosis gene modulators, apoptosis regulators, apurinic acid,
ara-CDP-DL-PTBA, arginine deaminase, asulacrine, atamestane,
atrimustine, axinastatin 1, axinastatin 2, axinastatin 3,
azasetron, azatoxin, azatyrosine, baccatin III derivatives,
balanol, batimastat, BCR/ABL antagonists, benzochlorins,
benzoylstaurosporine, beta lactam derivatives, beta-alethine,
betaclamycin B, betulinic acid, bFGF inhibitor, bicalutamide,
bisantrene, bisaziridinylspermine, bisnafide, bistratene A,
bizelesin, breflate, bropirimine, budotitane, buthionine
sulfoximine, calcipotriol, calphostin C, camptothecin derivatives,
canarypox LL-2, capecitabine, carboxamide-amino-triazole,
carboxyamidotriazole, CaRest M3, CARN 700, cartilage derived
inhibitor, carzelesin, casein kinase inhibitors (ICOS),
castanospermine, cecropin B, cetrorelix, chlorins,
chloroquinoxaline sulfonamide, cicaprost, cis-porphyrin,
cladribine, clomifene analogues, clotrimazole, collismycin A,
collismycin B, combretastatin A4, combretastatin analogue,
conagenin, crambescidin 816, crisnatol, cryptophycin 8,
cryptophycin A derivatives, curacin A, cyclopentanthraquinones,
cycloplatam, cypemycin, cytarabine ocfosfate, cytolytic factor,
cytostatin, dacliximab, decitabine, dehydrodidemnin B, deslorelin,
dexifosfamide, dexrazoxane, dexverapamil, diaziquone, didemnin B,
didox, diethylnorspermine, dihydro-5-azacytidine, dihydrotaxol,
9-dioxamycin, diphenyl spiromustine, docosanol, dolasetron,
droloxifene, dronabinol, duocannycin SA, ebselen, ecomustine,
edelfosine, edrecolomab, eflornithine, elemene, emitefur,
epirubicin, epristeride, estramustine analogue, estrogen agonists,
estrogen antagonists, etanidazole, etoposide phosphate, exemestane,
fadrozole, fazarabine, fenretinide, filgrastim, fmasteride,
flavopiridol, flezelastine, fluasterone, fludarabine,
fluorodaunorunicin hydrochloride, forfenimex, formestane,
fostriecin, fotemustine, gadolinium texaphyrin, gallium nitrate,
galocitabine, ganirelix, gelatinase inhibitors, gemcitabine,
glutathione inhibitors, hepsulfam, heregulin, hexamethylene
bisacetamide, hypericin, ibandronic acid, idarubicin, idoxifene,
idramantone, ilmofosine, ilornastat, imidazoacridones, imiquimod,
immunostimulant peptides, insulin-like growth factor-1 receptor
inhibitor, interferon agonists, interferons, interleukins,
iobenguane, iododoxorubicin, ipomeanol, 4-irinotecan, iroplact,
irsogladine, isobengazole, isohomohalicondrin B, itasetron,
jasplakinolide, kahalalide F, lamellarin-N triacetate, lanreotide,
leinamycin, lenograstim, lentinan sulfate, leptolstatin, letrozole,
leukemia inhibiting factor, leukocyte alpha interferon,
leuprolide+estrogen+progesterone, leuprorelin, levamisole,
liarozole, linear polyamine analogue, lipophilic disaccharide
peptide, lipophilic platinum compounds, lissoclinamide 7,
lobaplatin, lombricine, lometrexol, lonidamine, losoxantrone,
lovastatin, loxoribine, lurtotecan, lutetium texaphyrin,
lysofylline, lytic peptides, maitansine, mannostatin A, marimastat,
masoprocol, maspin, matrilysin inhibitors, matrix metalloproteinase
inhibitors, menogaril, merbarone, meterelin, methioninase,
metoclopramide, inhibitor, mifepristone, miltefosine, mirimostim,
mismatched double stranded RNA, mitoguazone, mitolactol, mitomycin
analogues, mitonafide, mitotoxin fibroblast growth factor-saporin,
mitoxantrone, mofarotene, molgramostim, monoclonal antibody, human
chorionic gonadotrophin, monophosphoryl lipid A+myobacterium cell
wall sk, mopidamol, multiple drug resistance genie inhibitor,
multiple tumor suppressor 1-based therapy, mustard anticancer
agent, mycaperoxide B, mycobacterial cell wall extract,
myriaporone, N-acetyldinaline, N-substituted benzamides, nafarelin,
nagrestip, naloxone+pentazocine, napavin, naphterpin, nartograstim,
nedaplatin, nemorubicin, neridronic acid, neutral endopeptidase,
nilutamide, nisamycin, nitric oxide modulators, nitroxide
antioxidant, nitrullyn, O6-benzylguanine, octreotide, okicenone,
oligonucleotides, onapristone, ondansetron, ondansetron, oracin,
oral cytokine inducer, ormaplatin, osaterone, oxaliplatin,
oxaunomycin, paclitaxel analogues, paclitaxel derivatives,
palauamine, palmitoylrhizoxin, pamidronic acid, panaxytriol,
panomifene, parabactin, pazelliptine, pegaspargase, peldesine,
pentosan polysulfate sodium, pentostatin, pentrozole, perflubron,
perfosfamide, perillyl alcohol, phenazinomycin, phenylacetate,
phosphatase inhibitors, picibanil, pilocarpine hydrochloride,
pirarubicin, piritrexim, placetin A, placetin B, plasminogen
activator inhibitor, platinum complex, platinum compounds,
platinum-triamine complex, porfimer sodium, porfiromycin, propyl
bis-acridone, prostaglandin J2, proteasome inhibitors, protein
A-based immune modulator, protein kinase C inhibitor, protein
kinase C inhibitors, microalgal, protein tyrosine phosphatase
inhibitors, purine nucleoside phosphorylase inhibitors, purpurins,
pyrazoloacridine, pyridoxylated hemoglobin polyoxyethylene
conjugate, raf antagonists, raltitrexed, ramosetron, ras farnesyl
protein transferase inhibitors, ras inhibitors, ras-GAP inhibitor,
retelliptine demethylated, rhenium Re 186 etidronate, rhizoxin,
ribozymes, retinamide, rogietimide, rohitukine, romurtide,
roquinimex, rubiginone B1, ruboxyl, safingol, saintopin, SarCNU,
sarcophytol A, sargramostim, Sdi 1 mimetics, semustine, senescence
derived inhibitor 1, sense oligonucleotides, signal transduction
inhibitors, signal transduction modulators, single chain antigen
binding protein, sizofiran, sobuzoxane, sodium borocaptate, sodium
phenylacetate, solverol, somatomedin binding protein, sonermin,
sparfosic acid, spicamycin D, spiromustine, splenopentin,
spongistatin 1, squalamine, stem cell inhibitor, stem-cell division
inhibitors, stipiamide, stromelysin inhibitors, sulfmosine,
superactive vasoactive intestinal peptide antagonist, suradista,
suramin, swainsonine, synthetic glycosaminoglycans, tallimustine,
tamoxifen ethiodide, tauromustine, tazarotene, tecogalan sodium,
tegafur, tellurapyrylium, telomerase inhibitors, temoporfin,
temozolomide, teniposide, tetrachlorodecaoxide, tetrazomine,
thaliblastine, thalidomide, thiocoraline, thrombopoietin,
thrombopoietin mimetic, thymalfasin, thymopoietin receptor agonist,
thymotrinan, thyroid stimulating hormone, tin ethyl etiopurpurin,
tirapazamine, titanocene dichloride, topotecan, topsentin,
toremifene, totipotent stem cell factor, translation inhibitors,
tretinoin, triacetyluridine, triciribine, trimetrexate,
triptorelin, tropisetron, turosteride, tyrosine kinase inhibitors,
tyrphostins, UBC inhibitors, ubenimex, urogenital sinus-derived
growth inhibitory factor, urokinase receptor antagonists,
vapreotide, variolin B, vector system, erythrocyte gene therapy,
velaresol, veramine, verdins, verteporfin, vinorelbine, vitaxin,
vorozole, zanoterone, zeniplatin, zilascorb, zinostatin
stimalamer.
[0217] Anti-cancer supplementary potentiating agents: tricyclic
anti-depressant drugs (e.g., imipramine, desipramine,
amitryptyline, clomiprainine, trimipramine, doxepin, nortriptyline,
protriptyline, amoxapine and maprotiline), non-tricyclic
anti-depressant drugs (e.g., sertraline, trazodone and citalopram),
Ca.sup.++ antagonists (e.g., verapamil, nifedipine, nitrendipine
and caroverine), calmodulin inhibitors (e.g., prenylamine,
trifluoroperazine and clomipramine), amphotericin B, triparanol
analogues (e.g., tamoxifen), antiarrhythmic drugs (e.g.,
quinidine), antihypertensive drugs (e.g., reserpine), thiol
depleters buthionine and sulfoximine) and Multiple Drug Resistance
reducing agents such as Cremaphor EL.
[0218] Antineutropenic: filgrastim, lenograstim, molgramostim,
regramostim, sargramostim.
[0219] Antiobsessional agent: fluvoxamine maleate.
[0220] Antiparasitic: abamectin, clorsulon, ivermectin.
[0221] Antiparkinsonian: benztropine mesylate, biperiden, biperiden
hydrochloride, biperiden lactate, carmantadine, ciladopa
hydrochloride, dopamantine, ethopropazine hydrochloride,
lazabemide, levodopa, lometraline hydrochloride, mofegiline
hydrochloride, naxagolide hydrochloride, pareptide sulfate,
procyclidine hydrochloride, quinetorane hydrochloride, ropinirole
hydrochloride, selegiline hydrochloride, tolcapone, trihexyphenidyl
hydrochloride, antiperistaltic; difenoximide hydrochloride,
difenoxin, diphenoxylate hydrochloride, fluperamide, lidamidine
hydrochloride, loperamide hydrochloride, malethamer, nufenoxole,
paregoric.
[0222] Antipneumocystic; atovaquone.
[0223] Antiproliferative agent: piritrexim isethionate.
[0224] Antiprostatic hypertrophy: sitogluside.
[0225] Antiprotozoal: amodiaquine, azanidazole, bamnidazole,
carnidazole, chlortetracycline bisulfate, chlortetracycline
hydrochloride, flubendazole, flunidazole, halofuginone
hydrobromide, imidocarb hydrochloride, ipronidazole, metronidazole,
misonidazole, moxnidazole, nitarsone, partricin, puromycin,
puromycin hydrochloride, ronidazole, sulnidazole, tinidazole.
[0226] Antipruritic: cyproheptadine hydrochloride, methdilazine,
methdilazine hydrochloride, trimeprazine tartrate.
[0227] Antipsoriatic: acitretin, anthralin, azaribine,
calcipotriene, cycloheximide, enazadrem phosphate, etretinate,
liarozole fumarate, lonapalene, tepoxalin.
[0228] Antipsychotic: acetophenazine maleate, alentemol
hydrobromide, alpertine, azaperone, batelapine maleate, benperidol,
benzindopyrine hydrochloride, brofbxine, bromperidol, bromperidol
decanoate, butactamol hydrochloride, butaperazine, butaperazine
maleate, carphenazine maleate, carvotroline hydrochloride,
chlorpromazine, chlorpromazine hydrochloride, chlorprothixene,
cinperene, cintriamide, clomacran phosphate, clopenthixol,
clopimozide, clopipazan mesylate, cloroperone hydrochloride,
clothiapine, clothixamide maleate, clozapine, cyclophenazine
hydrochloride, droperidol, etazolate hydrochloride, fenimide,
flucindole, flumezapine, fluphenazine decanoate, fluphenazine
enanthate, fluphenazine hydrochloride, fluspiperone, fluspirilene,
flutroline, gevotroline hydrochloride, halopemide, haloperidol,
haloperidol decanoate, iloperidone, imidoline hydrochloride,
lenperone, mazapertine succinate, mesoridazine, mesoridazine
besylate, metiapine, milenperone, milipertine, molindone
hydrochloride, naranol hydrochloride, neflumozide hydrochloride,
ocaperidone, olanzapine, oxiperomide, penfluridol, pentiapine
maleate, perphenazine, pimozide, pinoxepin hydrochloride,
pipamperone, piperacetazine, pipotiazine palniitate, piquindone
hydrochloride, prochlorperazine edisylate, prochlorperazine
maleate, promazine hydrochloride, remoxipride, remoxipride
hydrochloride, rimcazole hydrochloride, seperidol hydrochloride,
sertindole, setoperone, spiperone, thioridazine, thioridazine
hydrochloride, thiothixene, thiothixene hydrochloride, tioperidone
hydrochloride, tiospirone hydrochloride, trifluoperazine
hydrochloride, trifluperidol, triflupromazine, triflupromazine
hydrochloride, ziprasidone hydrochloride.
[0229] Antirheumatic: auranofin, aurothioglucose, bindarit,
lobenzarit sodium, phenylbutazone, pirazolac, prinomide
tromethamine, seprilose.
[0230] Antischistosomal: becanthone hydrochloride, hycanthone,
lucanthone hydrochloride, niridazole, oxamniquine, pararosaniline
pamoate, teroxalene hydrochloride.
[0231] Antiseborrheic: chloroxine, piroctone, piroctone olamine,
resorcinol monoacetate, antisecretory: arbaprostil, deprostil,
fenoctimine sulfate, octreotide, octreotide acetate, omeprazole
sodium, rioprostil, trimoprostil.
[0232] Antispasmodic: stilonium tizanidine hydrochloride.
[0233] Antithrombotic: anagrelide hydrochloride, bivaliradin,
dalteparin sodium, danaparoid sodium, dazoxiben, hydrochloride,
efegatran sulfate, enoxaparin sodium, ifetroban, ifetroban sodium,
tinzaparin sodium, trifenagrel.
[0234] Antitussive: benzonatate, butamirate citrate, chlophedianol
hydrochloride, codeine polistirex, codoxime, dextromethorphan,
dextromethorphan hydrobromide, dextromethorphan polistirex, ethyl
dibunate, guaiapate, hydrocodone bitartrate, hydrocodone
polistirex, levopropoxyphene napsylate, noscapine, pemerid nitrate,
pipazethate, suxemerid sulfate.
[0235] Anti-ulcerative: aceglutamide aluminum, cadexomer iodine,
cetraxate hydrochloride, enisoprost, isotiquimide, lansoprazole,
lavoltidine succinate, misoprostol, nizatidine, nolinium bromide,
pantoprazole, pifarnine, pirenzepine hydrochloride, rabeprazole
sodium, remiprostol, roxatidine acetate hydrochloride, sucralfate,
sucrosofate potassium, tolimidone.
[0236] Anti-urolithic: cysteamine, cysteamine hydrochloride,
tricitrates.
[0237] Appetite suppressant: dexfenfluramine hydrochloride,
phendimetrazine tartrate, phentermine hydrochloride.
[0238] Benign prostatic hyperplasia therapy agent: tamsulosin
hydrochloride.
[0239] Blood glucose regulators: human insulin, glucagon,
tolazamide, tolbutamide, chloropropamide, acetohexamide and
glipizide.
[0240] Bone resorption inhibitor: alendronate sodium, etidronate
disodium, pamidronate disodium.
[0241] Bronchodilator: albuterol, albuterol sulfate, azanator
maleate, bamifylline hydrochloride, bitolterol mesylate, butaprost,
carbuterol hydrochloride, clorprenaline hydrochloride, colterol
mesylate, doxaprost, doxofylline, dyphylline, line, ephedrine,
ephedrine hydrochloride, fenoterol, fenprinast hydrochloride,
guaithylline, hexoprenaline sulfate, hoquizil hydrochloride,
ipratropium bromide, isoetharine, isoetharine hydrochloride,
isoetharine mesylate, isoproterenol hydrochloride, isoproterenol
sulfate, metaproterenol polistirex, metaproterenol sulfate,
nisbuterol mesylate, oxtriphylline, picumeterol fumarate, piquizil
hydrochloride, pirbuterol acetate, pirbuterol hydrochloride,
procaterol hydrochloride, pseudoephedrine sulfate, quazodine,
quinterenol sulfate, racepinephrine, racepinephrine hydrochloride,
reproterol hydrochloride, rimiterol hydrobromide, salmeterol,
salmeterol xinafoate, soterenol hydrochloride, sulfonterol
hydrochloride, suloxifen oxalate, terbutaline sulfate,
theophylline, xanoxate sodium, zindotrine, zinterol
hydrochloride.
[0242] Carbonic anhydrase inhibitor: acetazolamide, acetazolamide
sodium, dichlorphenamide, dorzolamide hydrochloride, methazolamide,
sezolamide hydrochloride.
[0243] Cardiac depressant: acecainide hydrochloride, acetylcholine
chloride, actisomide, adenosine, amiodarone, aprindine, aprindine
hydrochloride, artilide fumarate, azimilide
[0244] Dihydrochloride, bidisomide, bucainide maleate, bucromarone,
butoprozine hydrochloride, capobenate sodium, capobenic acid,
cifenline, cifenline succinate, phosphate, disobutamide,
disopyramide, disopyramide phosphate, dofetilide, drobutine,
edifolone acetate, emilium tosylate, encainide hydrochloride,
flecainide acetate, ibutilide fumarate, indecainide hydrochloride,
ipazilide fumarate, lorajmine hydrochloride, lorcainide
hydrochloride, meobentine sulfate, mexiletine hydrochloride,
modecainide, moricizine, oxiramide, pirmenol hydrochloride,
pirolazamide, pranolium chloride, procainamide hydrochloride,
propafenone hydrochloride, pyrinoline, quindonium bromide,
quinidine gluconate, quinidine sulfate, recainam hydrochloride,
recainam tosylate, risotilide hydrochloride, ropitoin
hydrochloride, sematilide hydrochloride, suricainide maleate,
tocainide, tocainide hydrochloride, transcainide.
[0245] Cardioprotectant: dexrazoxane, draflazine.
[0246] Cardiotonic: actodigin, amrinone, bemoradan, butopamine,
carbazeran, carsatrin succinate, deslanoside, digitalis, digitoxin,
digoxin, dobutamine, dobutamine hydrochloride, dobutamine
lactobionate, dobutamine tartrate, enoximone, imazodan
hydrochloride, indolidan, isomazole hydrochloride, levdobutamine
lactobionate, lixazinone sulfate, medorinone, milrinone, pelrinone
hydrochloride, pimobendan, piroximone, prinoxodan, proscillaridin,
quazinone, tazolol hydrochloride, vesnarinone.
[0247] Cardiovascular agent: dopexamine, dopexamine
hydrochloride.
[0248] Choleretic: dehydrocholic acid, fencibutirol, hymecromone,
piprozolin, sincalide, tocamphyl.
[0249] Cholinergic: aceclidine, bethanechol chloride, carbachol,
demecarium bromide, dexpanthenol, echothiophate iodide,
isofluorophate, methacholine chloride, neostigmine bromide,
neostigmine methylsulfate, physostigmine, physostigmine salicylate,
physostigmine sulfate, pilocarpine, pilocarpine hydrochloride,
pilocarpine nitrate, pyridostigmine bromide.
[0250] Cholinergic agonist: xanomeline, xanomeline tartrate.
[0251] Cholinesterase deactivator: obidoxime chloride, pralidoxime
chloride, pralidoxime iodide, pralidoxime mesylate.
[0252] Coccidiostat: arprinocid, narasin, semduramicin,
semduramicin sodium.
[0253] Dognition adjuvant: ergoloid mesylates, piracetam,
pramiracetam hydrochloride, pramiracetam sulfate, tacrine
hydrochloride.
[0254] Cognition enhancer: besipirdine hydrochloride, linopirdine,
sibopirdine
[0255] Depressant: omeprazole.
[0256] Diagnostic aid: aminohippurate sodium, anazolene sodium,
arclofenin, arginine, bentiromide, benzylpenicilloyl polylysine,
butedronate tetrasodium, butilfenin, coccidioidin, corticorelin
ovine triflutate, corticotropin, repository, corticotropin zinc
hydroxide, diatrizoate meglumine, diatrizoate sodium, diatrizoic
acid, diphtheria toxin for schick test, disofenin, edrophonium
chloride, ethiodized oil, etifenin, exametazime, ferristenc,
ferumoxides, ferunioxsil, fluorescein, fluorescein sodium,
gadobenate dimeglumine, gadoteridol, gadodiamide, gadopentetate
dimegiumine, gadoversetamide, histoplasmin, impromidine
hydrochloride, indigotindisulfonate sodium, indocyanine green,
lobenguane sulfate I.sup.123, iobenzamic acid, iocarmate meglumine,
locarmic acid, iocetamic acid, iodamide, lodamide megiumine,
iodipamide meglumine, iodixanol, iodoxamate meglumine, iodoxamic
acid, ioglicic acid, ioglucol, ioglucomide, ioglycamic acid,
iogulamide, lohexol, iomeprol, iopamidol, iopanoic acid, iopentol,
iophendylate, iprofenin, iopronic acid, ioprocemic acid, iopydol,
iopydone, iosefamic acid, ioseric acid, iosulamide megiumine,
iosumetic acid, iotasul, iotetric acid, iothalamate meglumine,
iothalamate sodium, iothalamic acid, iotrolan, iotroxic acid,
ioversol, ioxaglate meglumine, ioxagiate sodium, ioxaglic acid,
ioxitan, ioxotrizoic acid, ipodate calcium, ipodate sodium,
isosulfan blue, leukocyte typing serum, lidofenin, mebrofenin,
megiumine, metrizamide, metrizoate sodium, metyrapone, metyrapone
tartrate, mumps skin test antigen, pentetic acid, propyliodone,
quinaldine blue, sermorelin acetate, sodium iodide I.sup.123,
sprodiamide, stannous pyrophosphate, stannous sulfur colloid,
succimer, teriparatide acetate, tetrofosmin, tolbutamide sodium,
tuberculin, tyropanoate sodium, xylose.
[0257] Diuretic: ambuphylline, ambuside, amiloride hydrochloride,
azolimine, azosemide, brocrinat, bumetanide, chlorothiazide,
chlorthalidone, clazolimine, clorexolone, ethacrynate sodium,
ethacrynic acid, etozolin, fenquizone, furosemide,
hydrochlorothiazide, isosorbide, mannitol, mefruside, ozolinone,
piretanide, spiroxasone, torsemide, triamterene, triflocin,
urea.
[0258] Dopaminergic agent: ibopamine.
[0259] Ectoparasiticide: permethrin.
[0260] Emetic: apomorphine hydrochloride.
[0261] Enzyme inhibitor: acetohydroxamic acid, alrestatin sodium,
aprotinin, benazepril hydrochloride, benazeprilat, benurestat,
bromocriptine, bromocriptine mesylate, cilastatin, sodium,
fluorofamide, lergotrile, lergotrile mesylate, levcycloserine,
pentopril, pepstatin, perindopril, polignate sodium, sodium
amylosulfate, sorbinit, spirapril hydrochloride, spiraprilat,
taleranol, teprotide, tolfamide, zofenopril calcium.
[0262] Estrogen: chlorotrianisene, dienestrol, diethylstilbestrol,
diethylstilbestrol diphosphate, equilin, estradiol, estradiol
cypionate, estradiol enanthate, estradiol undecylate, estradiol
valerate, estrazinol hydrobromide, estriol, estrofurate, estrogens,
conjugated, estrogens, esterified, estrone, estropipate, ethinyl
estradiol, fenestrel, mestranol, nylestriol, quinestrol.
[0263] Fibrinolytic: anistreplase, bisobrin lactate, brinolase.
[0264] Free oxygen radical scavenger: pegorgotein.
[0265] Gastrointestinal motility agents: cisapride (PROPULSID.TM.),
metoclopramide (REGLAN.TM.), hyoscyamine (LEVSIN.TM.).
[0266] Glucocorticoid: amcinonide, beclomethasone dipropionate,
betamethasone, betamethasone acetate, betamethasone benzoate,
betamethasone dipropionate, betamethasone sodium phosphate,
betamethasone valerate, carbenoxolone sodium, clocortolone acetate,
clocortolone pivalate, cloprednol, corticotropin, corticotropin,
repository, corticotropin zinc hydroxide, cortisone acetate,
cortivazol, descinolone acetonide, dexamethasone, dexamethasone
sodium phosphate, diflucortolone, diflucortolone pivalate,
flucloronide, flumethasone, flumethasone pivalate, flunisolide,
fluocinolone acetonide, fluocinonide, fluocortolone, fluocortolone
caproate, fluorometholone, fluperolone acetate, fluprednisolone,
fluprednisolone valerate, flurandrenolide, formocortal,
hydrocortisone, hydrocortisone acetate, hydrocortisone buteprate,
hydrocortisone butyrate, hydrocortisone sodium phosphate,
hydrocortisone sodium succinate, hydrocortisone valerate,
medrysone, methylprednisolone, methylprednisolone acetate,
methylprednisoloime sodium phosphate, methylprednisolone sodium
succinate, nivazol, paramethasone acetate, prednicarbate,
prednisolone, prednisolone acetate, prednisolone hemisuccinate,
prednisolone sodium phosphate, prednisolone sodium succinate,
prednisolone tebutate, prednisone, prednival, ticabesone
propionate, tralonide, triamcinolone, triamcinolone acetonide,
triamcinolone acetonide sodium, triamcinolone diacetate,
triamcinolone hexacetonide.
[0267] Gonad-stimulating principle: buserelin acetate, clomiphene
citrate, ganirelix acetate, gonadorelin acetate, gonadorelin
hydrochloride, gonadotropin, chorionic, menotropins.
[0268] Hair growth stimulant: minoxidil.
[0269] Hemostatic: aminocaproic acid, oxamarin hydrochloride,
sulmarin, thrombin, tranexarnic acid.
[0270] Histamine 112 receptor antagonists: ranitidine (ZANTAC.TM.),
famotidine (PEPCID.TM.), cimetidine (TAGAMET.TM.), nizatidine
(AXID.TM.).
[0271] Hormone: diethylstilbestrol, progesterone, 17 hydroxy
progesterone, medroxyprogesterone, norgestrel, norethynodrel,
estradiol, megestrol (megace), norethindrone, levonorgestrel,
ethyndiol, ethinyl estradiol, mestranol, estrone, equilin, 17 alpha
dihydroequilin, equilenin, 17 alpha dihydroequilenin, 17 alpha
estradiol, 17 beta estradiol, leuprolide (LUPRON.TM.), glucagon,
testolactone, clomiphene, human menopausal gonadotropins, human
chorionic gonadotropin, urofollitropin, bromocriptine, gonadorelin,
luteinizing hormone releasing hormone and analogs, gonadotropins,
danazol, testosterone, dehydroepiandrosterone, androstenedione,
dihydroestosterone, relaxin, oxytocin, vasopressin,
folliculostatin, follicle regulatory protein, gonadocirinins,
oocyte maturation inhibitor, insulin growth, factor, follicle
stimulating hormone, luteinizing hormone, tamoxifen, corticorelin
ovine triftutate, cosyntropin, metogest, pituitary, posterior,
seractide acetate, somalapor, somatrem, somatropin, somenopor,
somidobove.
[0272] Hypocholesterolemic: lifibrol.
[0273] Hypoglycemic: darglitazone sodium: glimepiride.
[0274] Hypolipidemic: azalanstat dihydrochloride, colestolone,
surfomer, xenalipin.
[0275] Hypotensive: viprostol.
[0276] Hmgcoa reductase inhibitors: lovastatin (MEVACOR.TM.),
simvastatin (ZOCOR.TM.), pravastatin (PRAVACHOL.TM.), fluvasatin
(LESCOL.TM.).
[0277] Immunizing agent: antirabies serum, antivenin (latrodectus
mactans), antivenin (micrurus fulvius), antivenin (crotalidae)
polyvalent, BCG vaccine, botulism antitoxin, cholera vaccine,
diphtheria antitoxin, diphtheria toxoid, diphtheria toxoid
adsorbed, globulin, immune, hepatitis b immune globulin, hepatitis
B virus vaccine inactivated, influenza virus vaccine, measles virus
vaccine live, meningococcal polysaccharide vaccine group A,
meningococcal polysaccharide vaccine group C, mumps virus vaccine
live, pertussis immune globulin, pertussis vaccine, pertussis
vaccine adsorbed, plague vaccine, poliovirus vaccine inactivated,
poliovinis vaccine live oral, rabies immune globulin, rabies
vaccine, Rh.sub.o (D) immune globulin, rubella virus vaccine live,
smallpox vaccine, tetanus antitoxin, tetanus immune globulin,
tetanus toxoid, tetanus toxoid adsorbed, typhoid vaccine, yellow
fever vaccine, vaccinia immune globulin, varicella-zoster immune
globulin.
[0278] Immunomodulator: dimepranol acedoben, imiquimod, interferon
beta-Ib, lisofylline, mycophenolate mofetil, prezatide copper
acetate.
[0279] Immunoregulator: azarole, fanetizole mesylate, frentizole,
oxamisole hydrochloride, ristianol phosphate, thymopentin,
tilomisole.
[0280] Immunostimulant: loxoribine, teceleukin.
[0281] Immunosuppressant: azathioprine, azathioprine sodium,
cyclosporine, daltroban, gusperimus trihydrochloride, sirolimus,
tacrolimus.
[0282] Impotence therapy adjunct: delequamine hydrochloride.
[0283] Inhibitor: acarbose, atorvastatin calcium, benserazide,
brocresine, carbidopa, clavulanate potassium, dazmegrel,
docebenone, epoprostenol, epoprostenol sodium, epristeride,
fmasteride, flurbiprofen sodium, furegrelate sodium, lufironil,
miglitol, orlistat, pimagedine hydrochloride, pirmagrel,
ponalrestat, ridogrel, sulbactam benzathine, sulbactampivoxil,
sulbactam sodium, suronacrine maleate, tazobactam, tazobactam
sodium, ticlopidine hydrochloride, tirilazad mesylate, tolrestat,
velnacrine maleate, zifrosilone, zileuton.
[0284] Keratolytic: alcloxa, aldioxa, benzoyl peroxide,
dibenzothiophene, etarotene, isotretinoin, motretinide, picotrin
diolamine, resorcinol, resorcinol monoacetate, salicylic acid,
sumarotene, tazarotene, tetroquinone, tretinoin.
[0285] LHRL agonist: destorelin, goserelin, histrelin, lutrelin
acetate, nafaretin acetate.
[0286] Liver disorder treatment: malotilate.
[0287] Luteolysin: fenprostalene.
[0288] Memory adjuvant: dimoxamine hydrochloride, ribaminol.
[0289] Mental performance enhancer: aniracetam.
[0290] Mood regulator: fengabine.
[0291] Mucolytic: acetylcysteine, carbocysteine, domiodol.
[0292] Mucosal protective agents: misoprostol (CYTOTEC.TM.).
[0293] Mydriatic: berefrine.
[0294] Nasal decongestant: nemazoline hydrochloride,
pseudoephedrine polistirex.
[0295] Neuroleptic: duoperone fumarate, risperidone.
[0296] Neuromuscular blocking agent: atracurium besylate,
cisatracurium besylate, doxacurium chloride, gallamine
triethiodide, metocurine iodide, mivacurium chloride, pancuronium
bromide, pipecuronium bromide, rocuronium bromide, succinylcholine
chloride, tubocurarine chloride, vecuronium bromide.
[0297] Neuroprotective: dizocilpine maleate.
[0298] NMDA antagonist: selfotel.
[0299] Non-hormonal sterol derivative: pregnenolone succinate.
[0300] Oxytocic: carboprost, carboprost methyl, carboprost
tromethamine, dinoprost, dinoprost tromethamine, dinoprostone,
ergonovine maleate, meteneprost, methylergonovine maleate,
oxytocin, sparteine sulfate.
[0301] Plasminogen activator: alteplase, urokinase.
[0302] Platelet activating factor antagonist: lexipafant.
[0303] Platelet aggregation inhibitor: acadesine, beraprost,
beraprost sodium, ciprostene calcium, itazigrel, lifarizine,
oxagrelate.
[0304] Post-stroke and post-head trauma treatment: citicoline
sodium.
[0305] Potentiator: pentostatin, talopram hydrochloride.
[0306] Progestin: algestone acetophenide, amadinone acetate,
anagestone acetate, chlormadinone acetate, cingestol, clogestone
acetate, clomegestone acetate, desogestrel, dimethisterone,
dydrogesterone, ethynerone, ethynodiol diacetate, etonogestrel,
fluorogestone acetate, gestaclone, gestodene, gestonorone caproate,
gestrinone, haloprogesterone, hydroxyprogesterone caproate,
levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone
acetate, methynodiol diacetate, norethindrone, norethindrone
acetate, norethynodrel, norgestimate, norgestomet, norgestrel,
oxogestone phenpropionate, progesterone, quingestanol acetate,
quingestrone, tigestol.
[0307] Prostaglandin: cloprostenol sodium, fluprostenol sodium,
gemeprost, prostalene, sulprostone.
[0308] Prostate growth inhibitor: pentomone.
[0309] Prothyrotropin: protirelin.
[0310] Psychotropic: minaprine.
[0311] Pulmonary surface: beractant, colfosceril palmitate.
[0312] Radioactive agent: fibrinogen I.sup.125, fludeoxyglucose
F.sup.18, fluorodopa F.sup.18, insulin I.sup.125, insulin
I.sup.131, iobenguane I.sup.123, iodipamide sodium I.sup.131,
iodoantipyrine I.sup.131, iodocholesterol I.sup.131, iodohippurate
sodium I.sup.123, iodohippurate sodium I.sup.125, iodohippurate
sodium I.sup.131, iodopyracet I.sup.125, iodopyracet I.sup.131,
iofetamine hydrochloride I.sup.123, iomethin I.sup.125, iomethin
I.sup.131, iothalamate sodium I.sup.125, iothalamate sodium
I.sup.131, iotyrosine I.sup.131, liothyronine I.sup.125,
liothyronine I.sup.131, merisoprol acetate Hg.sup.197, merisoprol
acetate Hg.sup.203, merisoprol Hg.sup.197, selenomethionine
Se.sup.75, technetium Tc.sup.99m antimony trisulfide colloid,
technetium Tc.sup.99m bicisate, technetium Tc.sup.99m disofenin,
technetium Tc.sup.99m etidronate, technetium Tc.sup.99m exaetazime,
technetium Tc.sup.99m furifosmin, technetium Tc.sup.99m gluceptate,
technetium Tc.sup.99m lidofenin, technetium Tc.sup.99m mebrofenin,
technetium Tc.sup.99m medronate, technetium Tc.sup.99m medronate
disodium, technetium Tc.sup.99m mertiatide, technetium Tc.sup.99m
oxidronate, technetium Tc.sup.99m pentetate, technetium Tc.sup.99m
pentetate calcium trisodium, technetium Tc.sup.99m sestamibi,
technetium Tc.sup.99m teboroxime, technetium Tc.sup.99m succimer,
technetium Tc.sup.99m sulfur colloid, technetium Tc.sup.99m
teboroxime, technetium Tc.sup.99m tetrofosmin, technetium
Tc.sup.99m tiatide, thyroxine I.sup.125, thyroxine I.sup.131,
tolpovidone I.sup.131, triolein I.sup.125, triolein I.sup.131.
[0313] Regulator: calcifediol, calcitonin, calcitriol, clodronic
acid, dihydrotachysterol, etidronic acid, oxidronic acid,
piridronate sodium, risedronate sodium, secalciferol.
[0314] Relaxant: adiphenine hydrochloride, alcuronium chloride,
aminophylline, azumolene sodium, baclofen, benzoctamine
hydrochloride, carisoprodol, chlorphenesin carbamate,
chlorzoxazone, cinflumide, cinnamedrine, clodanolene,
cyclobenzaprine hydrochloride, dantrolene, dantrolene sodium,
fenalamide, fenyripol hydrochloride, fetoxylate hydrochloride,
flavoxate hydrochloride, fletazepam, flumetramide, flurazepam
hydrochloride, hexafluorenium bromide, isomylamine hydrochloride,
lorbamate, mebeverine hydrochloride, mesuprine hydrochloride,
metaxalone, methocarbamol, methixene hydrochloride, nafomine
malate, nelezaprine maleate, papaverine hydrochloride,
pipoxolan.
[0315] Hydrochloride, quinctolate, ritodrine, ritodrine
hydrochloride, rolodine, theophylline sodium glycinate, thiphenamil
hydrochloride, xilobam.
[0316] Repartitioning agent: cimaterol.
[0317] Scabicide: amitraz, crotamiton.
[0318] Sclerosing agent: ethanolamine oleate, morrhuate sodium,
tribenoside.
[0319] Sedative: propiomazine.
[0320] Sedative-hypnotic: allobarbital, alonimid, alprazolam,
amobarbital sodium, bentazepam, brotizolam, butabarbital,
butabarbital sodium, butalbital, capuride, carbocloral, chloral
betaine, chloral hydrate, chlordiazepoxide hydrochloride,
cloperidone hydrochloride, clorethate, cyprazepam, dexclamol
hydrochloride, diazepam, dichloralphenazone, estazolam,
ethchlorvynol, etomidate, fenobam, flunitrazepam, fosazepam,
glutethimide, halazepam, lormetazepam, mecloqualone, meprobamate,
methaqualone, midaflur, paraldehyde, pentobarbital, pentobarbital
sodium, perlapine, prazepam, quazepam, reclazepam, roletamide,
secobarbital, secobarbital sodium, suproclone, thalidomide,
tracazolate, trepipam maleate, triazolam, tricetamide, triclofos
sodium, trimetozine, uldazepam, zaleplon, zolazepam hydrochloride,
zolpidem tartrate.
[0321] Selective adenosine a1 antagonist: apaxifylline.
[0322] Serotonin antagonist: altanserin tartrate, amesergide,
ketanserin, ritanserin.
[0323] Serotonin inhibitor: cinanserin hydrochloride, fenclonine,
fonazine mesylate, xylamidine tosylate.
[0324] Serotonin receptor antagonist: tropanserin
hydrochloride.
[0325] Steroid: dexamethasone aceflrate, mometasone furoate.
[0326] Stimulant: amfonelic acid, amphetamine sulfate, ampyzine
sulfate, arbutamine hydrochloride, azabon, caffeine, ceruletide,
ceruletide diethylamine, cisapride, dazopride fumarate,
dextroamphetamine, dextroamphetamine sulfate, difluanine
hydrochloride, dimefline hydrochloride, doxapram hydrochloride,
etryptamine acetate, ethamivan, fenethylline hydrochloride,
flubanilate hydrochloride, fluorothyl, histamine phosphate,
indriline hydrochloride, mefexamide, methamphetamine hydrochloride,
methylphenidate hydrochloride, pemoline, pyrovalerone
hydrochloride, xamoterol, xamoterol fumarate.
[0327] Suppressant: amfhutizole, coxchicine, tazofelone.
[0328] Symptomatic multiple sclerosis: fampridine.
[0329] Synergist: proadifen, hydrochloride.
[0330] Thyroid hormone: levothyroxine sodium, liothyronine sodium,
liotrix.
[0331] Thyroid inhibitor: methimazole, propylthiouracil.
[0332] Thyromimetic: thyromedan hydrochloride.
[0333] Tranquilizer: bromazepam, buspirone hydrochloride,
chlordiazepoxide, clazolam, clobazam, clorazepate dipotassium,
clorazepate monopotassium, demoxepam, dexmedetomidine, enciprazine
hydrochloride, gepirone hydrochloride, hydroxyphenamate,
hydroxyzine
[0334] Hydrochloride, hydroxyzine pamoate, ketazolam, lorazepam,
lorzafone, loxapine, loxapine succinate, medazepam hydrochloride,
nabilone, nisobamate, oxazepam, pentabamate, pirenperone,
ripazepam, roliprarn, sulazepam, taciamine hydrochloride,
temazepam, triflubazam, tybamate, valnoctamide.
[0335] Amyotrophic lateral sclerosis agents: riluzole.
[0336] Cerebral ischemia agents: dextrorphan hydrochloride.
[0337] Paget's disease agents: tiludronate disodium.
[0338] Unstable angina agents: tirofiban hydrochloride.
[0339] Uricosuric: benzbromarone, irtemazole, probenecid,
sulfinpyrazone.
[0340] Vasoconstrictor: angiotensin amide, felypressin,
methysergide, methysergide maleate.
[0341] Vasodilator: alprostadil, azaclorzine hydrochloride,
bamethan sulfate, bepridil hydrochloride, buterizine, cetiedil
citrate, chromonar hydrochloride, clonitrate, diltiazem
hydrochloride, dipyridamole, droprenilamine, erythrityl
tetranitrate, felodipine, flunarizine hydrochloride, fostedil,
hexobendine, inositol niacinate, iproxamine hydrochloride,
isosorbide dinitrate, isosorbide mononitrate, isoxsuprine
hydrochloride, lidoflazine, mefenidil, mefenidil fumarate,
mibefradil dihydrochloride, mioflazine hydrochloride, mixidine,
nafronyl oxalate, nicardipine hydrochloride, nicergoline,
nicorandil, nicotinyl alcohol, nifedipine, nimodipine, nisoldipine,
oxfenicine, oxprenolol hydrochloride, pentaerythritol tetranitrate,
pentoxifylline, pentrinitrol, perhexiline maleate, pindolol
pirsidomine, prenylamine, propatyl nitrate, suloctidil, terodiline
hydrochloride, tipropidil hydrochloride, tolazoline hydrochloride,
xanthinol niacinate.
[0342] Vulnerary: allantoin.
[0343] Wound healing agent: ersofermin.
[0344] Xanthine oxidase inhibitor: allopurinol, oxypurinol.
[0345] Other pharmaceutical agents include: 1-decpyrrolidinone,
1-dodecpyrrolidinone, 16.-fluoroestradiol, 16-epiestriol,
16.-gitoxin, 17.-estradiol, 17.-estradiol, 1alpha-hydroxyvitamin
D2,2'-nor-cGMP, 20-epi-1,25 dihydroxyvitamin D3, 22-oxacalcitriol,
2CVV, 3-isobutyl GABA, 6-FUDCA, 7-methoxytacrine, abamectin,
abanoquil, abecarnil, abiraterone, acadesine, acamprosate,
acarbose, aceclofenac, acemannan, acetomepregenol,
acetyl-L-carnitine, acetylcysteine, N-acetylmethadol, acifran,
acipimox, acitemate, acitretin, aclarubicin, aclatonium,
napadisilate, aconiazide, acrivastinet, adafenoxate, adapalene,
adatanserin, adecypenol, adefovir dipivoxil, adelmidrol,
ademetionine, adinazolam, adiposin, adozelesin, adrafinil,
alacepril, aladapcin, alaptide, albendazole, albolabrin,
aldecalmycin, aldesleukin, alendronic acid, alentemol,
alfacalcidol, alfuizosin, alglucerase, alinastine, alosetron, alpha
idosone, alprostadil, altretamine, altromycin B, ambamustine,
amelometasone, amesergide, amezinium metilsulfate, amfebutamone,
amidox, amifloxacin, amifostine, amiodarone, amisulpride,
analexanox, amlodipine, amlodipine, ampiroxicam, aminone,
amrubicin, amsacrine, amylin, amythianhcin, anagrelide, anakinra,
ananain, anaritide, anastrozole, andrographolide, anordrin,
apadoline, apafant, apaxifylline aphidicolin glycinate,
apracionidine, aprosulate sodium, aptiganel, apurinic acid,
aranidipine, arbekacin, arbidol, arbutamine, ardeparin sodium,
arecatannin B1, argatroban, aripiprazol, arotinolol, asimadoline,
aspalatone, asperfuran, aspoxicillin, astemizole, asulacrine,
atamestanie, atenolol, S-atevirdine, atosiban, atovaquone, atpenin
B, atrimustine, atrinositol, aureobasidin A, azadirachtine,
azasetron, azatyrosine, azelaic acid, azelastine, azelnidipine,
azimilide, azithromycin, azosemide, aztreonam, baccatin III,
bacoside A, bacoside B, bactobolamine, balazipone, balhimycin,
balofloxacin, balsalazide, bambuterol, baohuoside 1, bamidipine,
basifungin, batebulast, batimastat, beauvericin, becaplermin,
becliconazole, befloxatone, belfosdil, bellenamine, benflumetol,
benidipine, benzisoxazole, benzochlorins, benzoidazoxan,
benzoylstaurosporine, benztropine, bepridil, beractant, beraprost,
berlafenone, bertosamil, besipirdine, beta-alethine, betaclamycin
B, betamipron, betaxolol, betulinic acid, bevantolol, bicalutamide,
bifemelane, birnakalim, bimithil, binospirone, bioxalomycin alpha2,
biriperone, bis-benzimidazole A, bis-benzimidazole B, bisantrene,
bisaramil, bisaziridinylspermine, bisnafide, bisoprolol, bistramide
D, bistramide K, bistratene A, boldine, bopindolol, brefeldin,
breflate, brimonidine, bromfenac, bromperidol, bropirimine,
bucindolol, budesonide, budipine, budotitane, bunaprolast,
bunazosin, butenafine, buthionine sulfoximine, butixocort
propionate, cadexomer iodine, calanolide A, calcipotriol,
calphostin C, camonagrel, candesartan, candesartan cilexetil,
candoxatril, candoxatrilat, capecitabine, capromab, capsaicin,
captopril, carbazomycin C, carbetocin, carbovir,
carboxamide-amino-triazole, carboxyamidotriazole,
carboxymethylated.-1,3-glucan, carperitide, carteolol, carumonam,
carvedilol, carvotroline carzelesin castanospermine, cebaracetam,
cecropin B, cefcapene pivoxil, cefdaloxime pentexil tosilate,
cefdinir, cefditoren pivoxil, cefepime, cefetamet, cefetamet
pivoxil, cefixime, cefluprenam, cefmnetazole, cefmninox,
cefodizime, cefoselis, cefotetan, cefotiam, cefotiam hexetil,
cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime
proxetil, cefprozil, cefsulodin, cefteram, ceftibuten, cefiriaxone,
cefuroxime axetil, celastrol, celikalim, celiprolol, cepacidine A,
cericlamine, cerivastatin, ceronapril, certoparin sodium, cetiedil,
cetirizine, chloroorienticin A, chloroorienticin B,
chloroquinoxaline sulfonamide, cibenzoline, cicaprost, ciclesonide,
cicletanine, cicloprolol, cidofovir, cilansetron, cilazapril,
cilnidipine cilobradine, cilostazol, cimetropium bromide,
cinitapride, cinolazepam, cioteronel, ciprofibrate, ciprofloxacin,
ciprostene, cis-porphyrin, cisapride, cisatracurium besilate,
cistinexine, citalopram, citicoline, citreamicin alpha, cladribine,
clarithromycin, clausenamide, clebopride, clinafloxacin, clobazam,
clobetasone butyrate, clodronic acid, clomethiazole, clopidogrel,
clotrimazole, colestimide, colfosceril palmitate, collismycin A,
collismycin B, combretastatin A4, complestatin, conagenin,
contignasterol, contortrostatin, cosalane, costatolide, cotinine,
coumermycin A1, cucumariosid, curacin A, curdlan sulfate, curiosin,
cyclazosin, cyclic HPMPC, cyclobenzaprine, cyclobut A, cyclobut G,
cyclocapron, cycloplatam, cyclosin, cyclothialidine,
cyclothiazomycin, cypemycin, cyproterone, cytarabine ocfosfate,
cytochalasin B, dacliximab, dactimicin, daidzein, daidzin,
dalfopristin, dalteparin sodium, danaparoid, daphriodorin A,
dapiprazole, dapitant, darifenacin, darlucin A, darsidomine, ddUTP,
decitabine, deferiprone, deflazacort, dehydrodidemnin B,
dehydroepiandrosterone, delapril, delequamine, delfaprazine,
delmopinol, delphinidin, deoxypyridinoline, deprodone,
depsidomycin, deramciclane, dermatan sulfate, desflurane,
desirudin, deslorelin, desmopressin, desogestrel,
desoxoarniodarone, detajmium bitartrate, dexifosfamide,
dexketoprofen, dexloxiglumide, dexmedetomidine, dexpemedolac,
dexrazoxane, dexsotalol, dextrin 2-sulphate, dexverapamil,
dezinamide, dezocine, diaziquone, diclofenac digolil, diclofenac
potassium, dicranin, didemnin B, didox, dienogest,
diethylhomospermine, diethylnorspermine, dihydrexidine,
dihydro-5-azacytidine, dimethyl prostaglandin A1,
dimethylhomospermine, dimiracetam, dioxamycin, diphencyprone,
diphenyl spiromustine, diprafenone, dipropylnorspermine,
dirithromycin, discodermolide, disulfiram, ditekiren, docarpamine,
docosanol, 1-dofetilide, dolasetron, domitroban, dopexamine,
dorzolamide, dosmalfate, dotarizine, doxacurium chloride,
doxazosin, doxifluridine, doxofylline, draculin, draflazine,
droloxifene, dronabinol, drosperidone, drotaverine acephyllinate,
droxicam, ebiratide, ebrotidine, ebselen, ecabapide, ecabet,
ecadotril, ecdisteron, echicetin, echistatin, ecomustine,
ecteinascidin 722, ecteinascidin 729, ecteinascidin 743, edaravone,
edelfosine, edobacomab, edrecolomab, efegatran, eflornithine,
efonidipine, egualen, elcatonin, eletriptan, elgodipine, eliprodil,
eltenac, emakalim, emedastine, emiglitate, emitefur, emoctakin,
enadoline hydrochloride, enalapril, enazadrem, englitazone,
enlimomab, enoxacin, enoxaparin sodium, enoximone, entacapone,
enterostatin, epoprostenol, epoxymexrenone, epristeride,
eprosartan, eptastigmine, erdosteine, ersentilide, ersofermin,
erytlritol, esuprone, etanidazole, etanterol, ethacizin,
ethinylestradiol, etizolam, etodolac, etoposide phosphate,
etrabamine, everninomicin, examorelin, exemestane, fadrozole,
faeriefungin, famciclovir, fampridine, fantofarone, faropenem,
fasidotril, fasudil, fazarabine, fedotozine, felbamate,
fenofibrate, fenoldopam, fenretinide, fenspiride, fenticonazole,
fepradinol, ferpifosate sodium, ferristene, ferrixan, ferumoxsil,
fexofenadine, flavopiridol, flecainide, flerobuterol, fleroxacin,
flesinoxan, flezelastine, flobufen, flomoxef, florfenicol,
florifenine, flosatidil, fluasterone, fluconazole, fludarabine,
flumazenil, flumecinol, flumequine, flunarizine, fluocalcitriol,
fluorodaunorunicin hydrochloride, fluoxetine, R-fluoxetine,
S-fluparoxan, flupirtine, flurbiprofen axetil, flurithromycin,
fluticasone propionate, flutrimazole, fluvastatin, fluvoxamine,
forasartan, forfenimex, formestane, formoterol, formoterol,
R,R-fosfomycin, trometamol, fosinopril, fosphenytoin, fostriecin,
fotemustine, gabapentin, gadobenic acid, gadobutrol, gadodiamide,
gadodiamide-EOB-DTPA, gadolinium texaphyrin, gadoteric acid,
gadoteridol, gadoversetamide, galantamine, galdansetron,
gallopamil, galocitabine, gamolenic acid, ganirelix, gepirone,
gestrinone, girisopam, glaspimod, glaucocalyxin A, glutapyrone,
glycopine, glycopril, granisetron, grepafloxacin, halichondrin B,
halofantrine, halomon, halopredone, hatomamicin, hatomarubigin A,
hatomarubigin B, hatomarubigin C, hatomarubigin D, ibogaine,
ibopamine, ibudilast, ilmofosine, ilomastat, iloperidone, iloprost,
imidapril, imidazenil, indinavir, indolidan, indometacin farnesil,
indometacin, tropine ester, indoramin, inocoterone, inogatran,
inolimomab, interferon alfa, interferon alfa-2a, interferon
alfa-2B, interferon alfa-N1, interferon alfa-N3, interferon.,
interferon.-1 A1, interferon.-1B, interferon gamma-1A, interferon
gamma-1B, interferon omega, interferon, consensus, interleukin-1,
interleukin-1 alpha, interleukin-1., interleukin-10,
interleukin-11, interleukin-12, interleukin-12, interleukin-15,
interleukin-2, interleukin-3, interleukin-4, interleukin-5,
interleukin-7, interleukin-8, iobenguane, iobitridol,
iodoamiloride, iododoxorubicin, iofratol, iomeprol, iopentol,
iopromide, iotriside, ioversol, ioxilan, ipazilide, IpdR,
ipenoxazone, ipidacrine, ipomeanol, 4-ipriflavone, ipsapirone,
irbesartan, irinotecan, irloxacin, irsogladine, irtemazole,
isalsteine, isbogrel, isepamicin, isobengazole, isofloxythepin,
isohomohalicondrin B, isopropyl unoprostone, isradipine, itameline,
itasetron, itopride, itraconazole, ketoprofen, R-ketoprofen,
S-ketorolac, lactitol, lactivicin, laennec, lafutidine,
lamelrarin-N triacetate, lamifiban, lamivudine, lamotrigine,
lanoconazole, lanperisone, lanreotide, lansoprazole, latanoprost,
lateritin, laurocapram, lazabemide, lemefloxacin, leminoprazole,
leminoprazole, lenercept, lenograstim, lentinan sulfate, leptin,
leptolstatin, lercanidipine, lerisetron, lesopitron, letrazuril,
letrozole, leucomyzin, leuprorelin, leveromakalim, levetiracetam,
levobetaxolol, levobunolol, levobupivacaine, levocabastine,
levocamitine, levodropropizine, levofloxacin, levomoprolol,
levonorgestrel, levormeloxifene, levosimendan, levosulpiride,
linotroban, linsidomine, lintitript, lintopride, liothyronine
sodium, lirexapride, lisinopril, lobaplatin, lobucavir, lodoxamide,
lombricine, lomefloxacin, lomerizine, lometrexol, lonazolac,
lonidamine, loracarbef, loratadine, lorglumide, lornoxicam,
losartan, losigamone, losoxantrone, loteprednol, loviride,
loxoribine, lurtotecan, luteinizing hormone, lutetium, luzindole,
lydicamyein, lysofylline, lysostaphin, magainin 2 amide, magnolol,
mallotochromene, mallotojaponin, malotilate, mangafodipir,
manidipine, maniwamycin A, mannostatin A, manumycin E, manumycin F,
mapinastine, marimastat, masoprocol, maspin, massetolide,
meterelin, methoxatone, methylhistamine, R-alpha, methylinosine
monophosphate, methylprednisolone aceponate, methylprednisolone
suleptanate, metipamide, metoclopramide, metoprolol, S-metrifonate,
mibefradil, michellarnine B, microcolin A, midodrine, mifepristone,
milacemide, milameline, mildronate, milnacipran, milrinone,
miltefosine, minaprine, miokamycin, mipragoside, mirfentanil,
mirimostim, mirtazapine, misoprostol, mitoguazone, mitolactol,
mitonafide, mitoxantrone, mivacurium chloride, mivazerol,
mixanpril, mizolastine, mizoribine, moclobemide, modafinil,
moexipril, mofarotene, mofezolac, molgramostim, mometasone,
montirelin, mopidamol, moracizine, mosapramine, mosapride,
motilide, moxiraprine, moxonidine, nadifloxacin, nadroparin
calcium, nafadotride, nafamostat, nafarelin, naftopidil, naglivan,
nagrestip, nalmefene, naphterpin, napsagatran, naratriptan,
nartograstim, nasaruplase, nateplase, niperotidine, niravoline,
nisamycin, nisin, nisoldipine, nitazoxanide, nitecapone,
nitrendipine, nitrendipine, S-nitrofurantoin monohydrate,
nitrullyn, nizatidine, ofloxacin, okicenone, olanzapine,
olopatadine, olprinone, olsalazine, omeprazole, onapristone,
ondansetron, ondansetron, R-ontazolast, oracin, otenzepad,
oxaliplatin, oxamisole, oxandrolone, oxaprozin, oxaunomycin,
oxcarbazepine, oxiconazole, oxiracetam, oxodipine, ozagrel,
palauamine, palinavir, palmitoylrhizoxin, pamaqueside, pamicogrel,
pamidronic acid, panamesine, panaxytriol, panipenem, panipenum,
pannorin, panomifene, pantethine, pantoprazole, parabactin,
pamaparin sodium, paroxetine, parthenolide, pazelliptine,
pazufloxacin, pefloxacin, pegaspargase, peldesine, pemedolac,
pemirolast, penciclovir, pentafuside, pentamidine, pentamorphone,
pentigetide, pentosan, pentostatin, pentrozole, perflubron,
perfosfamide, pergolide, perindoprilat, perospirone, phenaridine,
phenazinomycin, phenserine, phensuccinal, phentolamine mesilate,
phenylacetate, phenylalanyl ketoconazole, picenadol, picibanil,
picroliv, picumeterol, pidotimod, pilocarpine hydrochloride,
pilsicainide, pimagedine, pimilprost, pimobendan, pinacidil,
pinocebrin, pioglitazone, pipecuronium bromide, pirarubicin,
piretanide, pirfenidone, piritrexim, pirlindole, pirmagrel,
pirmenol, pirodavir, pirodomast, piroxicam cinnamate,
propagermanium, propentofylline, propionylcamitine, L-propiram,
propiram+paracetamol, propiverine, propyl bis-acridone,
prostaglandin J2, prostratin, protegrin, protosufloxacin,
prulifloxacin, pyrazoloacridine, quazepam, quetiapine, quiflapon,
quinagolide, quinapril, quinfamide, quinupristin, raloxifene,
raltitrexed, ramatroban, ramipril, ramosetron, ranelic acid,
ranitidine bismuth citrate, ranolazine, recainam, regavirumab,
retaxin, repirinast, resinferatoxin, reticulon, reviparin sodium,
revizinone, ricasetron, rifabutin, rifapentine, rifaximin,
rilopirox, riluzole, rimantadine, rimexolone, rimoprogin,
riodipine, ripisartan, risedronic acid, rispenzepine, risperidone,
ritanserin, ritipenem, ritipenem acoxil, ritolukast, ritonavir,
rizatriptan benzoate, rohitukine, rokitamycin, ropinirole,
ropivacaine, roquinimex, roxatidine, roxindole, roxithromycin,
rubiginone B1, ruboxyl, rufloxacin, rupatidine, ruzadolane,
safingol, safironil, saintopin, salbutamol, R-salmeterol,
salmeterol, R-sainacedin, sameridine, sampatrilat, sanfetrinem,
saprisartan, sapropterin, saquinavir, sarcophytol A sargramostim,
sarpogrelate, saruplase, saterinone, satigrel, satumomab pendetide,
selegiline, selenium thiosemicarbazone, sematilide, semduramicin,
semotiadil, semustine, sermorelin, sertaconazole, sertindole,
sertraline, setiptiline, sevirumab, sevoflurane, sezolamide,
silipide, silteplase, simendan, simvastatin, sinnabidol,
sipatrigine, sirolimus, sizofuran, somatomedin B, somatomedin C,
somatrem, somatropin, sonermin, stalol, staurosporine, stavudine,
stepronin, sipiamide, stiripentol, stobadine, succibun, sucralfate,
sulfasalazine, sulfmosine, sulfoxamine, sulopenem, sultamicillin,
sultopride, sulukast, sumatriptan, symakalim, tandospirone, tapgen,
taprostene, tasosartan, tazanolast, tazarotene, teicoplanin,
telenzepine, tellurapyrylium, telmesteine, telmisartan, temocapril,
temoporfin, temozolomide, tenidap, teniposide, tenosal, tenoxicam,
tepirindole, tepoxalin, terazosin, terbinafine, terfenadine,
terflavoxate, terguride, terlakiren, terlipressin, terodiline,
tertatolol, testosterone baciclate, tetrachlorodecaoxide,
tetrazomine, thaliblastine, thalidomide, thiocoraline, thiofedrine,
thiomarinol, thioperamide, thyroid stimulating hormone, tiagabine,
tianeptine, tiapafant, tibolone, ticlopidine, tienoxolol,
tilisolol, tilnoprofen arbamel, tiludronic acid, tinzaparin sodium,
tiotropium bromide, tipredane, tiqueside, tirandalydigin,
tirapazamine, tirilazad, tirofiban, tiropramide, topsentin,
torasemide, toremifene, tosufloxacin, trafermin, trandolapril,
traxanox, tretinoin, tretinoin tocoferil, triacetyluridine,
tricaprilin, trichohyalin, trichosanthin, alpha, triciribine,
trientine, triflavin, trimegestone, triptorelin, troglitazone,
trombodipine, tropisetron, trospectomycin, trovafloxacin,
trovirdine, tucaresol, tulobuterol, tylogenin, urapidil, uridine
triphosphate, valaciclovir, valproate magnesium, valproate
semisodium, valsartan, vamicamide, vanadeine, vaninolol,
vapreotide, variolin B, velaresol, venlafaxine, veramine,
verapamil, S-verdins, veroxan, verteporfin, vesnarinone, vexibinol,
vigabatrin, vinbumine citrate, vinburnine resinate, vinconate,
vinorelbine, vinpocetine, vinpocetine citrate, vintoperol,
vinxaltine, voriconazole, vorozole, voxergolide, xemilofiban,
ximoprofen, yangambin, zabicipril, zacopride, zacopride,
R-zafirlukast, zalcitabine, zaleplon, zalospirone, zaltoprofen,
zanamivir, zankiren, zanoterone, zatebradine, zatosetron,
zenarestat, zeniplatin, zifrosilone, zilascorb, zileuton,
zinostatin stimalamer, ziprasidone, zoledronic acid, zolmitriptan,
zolpidem, zonisamide, zopiclone, zopiclone, S-zopolrestat,
zotepine.
Specific Examples of Antibacterials
[0346] When antibacterial activity is a desired property of the
disclosed ionic liquids, one or more of the ions in the disclosed
ionic liquids can be an antibacterial. That is the one or more
kinds of cations, one or more kinds of anions, or both cations and
anions can be an antibacterial. Many of suitable antibacterial have
already been disclosed herein (e.g., many QACs have antibacterial
properties). Further examples of suitable antibacterial agents
include, but are not limited to, acedapsone, acetosulfone sodium,
alamecin, alexidine, amdinocillin, amdinocillin pivoxil,
amicycline, amifloxacin, amifloxacin mesylate, amikacin, amikacin
sulfate, aminosalicylic acid, aminosalicylate sodium, amoxicillin,
amphomycin, ampicillin, ampicillin sodium, apalcillin sodium,
apramycin, aspartocin, astromicin sulfate, avilamycin, avoparcin,
azithromycin, azlocillin, azlocillin sodium, bacampicillin
hydrochloride, bacitracin, bacitracin methylene disalicylate,
bacitracin zinc, bambermycins, benzoylpas calcium, berythromycin,
betamicin sulfate, biapenem, biniramycin, biphenamine
hydrochloride, bispyrithione magsulfex, butikacin, butirosin
sulfate, capreomycin sulfate, carbadox, carbenicillin disodium,
cafbenicillin indanyl sodium, carbenicillin phenyl sodium,
carbenicillin potassium, carumonam sodium, cefaclor, cefadroxil,
cefamandole, cefamandole nafate, cefamandole sodium, cefaparole,
cefatrizine, cefazaflur sodium, cefazolin, cefazolin sodium,
cefbuperazone, cefdinir, cefepime, cefepime hydrochloride,
cefetecol, cefixime, cefmenoxime hydrochloride, cefmetazole,
cefmetazole sodium, cefonicid monosodium, cefonicid sodium,
cefoperazone sodium, ceforanide, cefotaxime sodium, cefotetan,
cefotetan disodium, cefotiam hydrochloride, cefoxitin, cefoxitin
sodium, cefpimizole, cefpimizole sodium, cefpiramide, cefpiramide
sodium, cefpirome sulfate, cefpodoxime proxetil, cefprozil,
cefroxadine, cefsulodin sodium, ceftazidime, ceftibuten,
ceftizoxime sodium, ceftriaxone sodium, cefuroxime, cefuroxime
axetil, cefuroxime pivoxetil, cefuroxime sodium, cephacetrile
sodium, cephalexin, cephalexin hydrochloride, cephaloglycin,
cephaloridine, cephalothin sodium, cephapirin sodium, cephradine,
cetocycline hydrochloride, cetophenicol, chloramphenicol,
chloramphenicol palmitate, chloramphenicol pantothenate complex,
chloramphenicol sodium succinate, chlorhexidine phosphanilate,
chloroxylenol, chlortetracycline bisulfate, chlortetracycline
hydrochloride, cinoxacin, ciprofloxacin, ciprofloxacin
hydrochloride, cirolemycin, clarithromycin, clinafloxacin
hydrochloride, clindamycin, clindamycin hydrochloride, clindamycin
palmitate hydrochloride, clindamycin phosphate, clofazimine,
cloxacillin benzathine, cloxacillin sodium, cloxyquin,
colistimethate sodium, colistin sulfate, coumermycin, coumermycin
sodium, cyclacillin, cycloserine, dalfopristin, dapsone,
daptomycin, demeclocycline, demeclocycline hydrochloride,
demecycline, denofungin, diaveridine, dicloxacillin, dicloxacillin
sodium, dihydrostreptomycin sulfate, dipyrithione, dirithromycin,
doxycycline, doxycycline calcium, doxycycline fosfatex, doxycycline
hyclate, droxacin sodium, enoxacin, epicillin, epitetracycline
hydrochloride, erythromycin, erythromycin acistrate, erythromycin
estolate, erythromycin ethylsuccinate, erythromycin gluceptate,
erythromycin lactobionate, erythromycin propionate, erythromycin
stearate, ethambutol hydrochloride, ethionamide, fleroxacin,
fludalanine, flumequine, fosfomycin, fosfomycin tromethamine,
fumoxicillin, furazolium chloride, furazolium tartrate, fusidate
sodium, fusidic acid, gentamicin sulfate, gloximonam, gramicidin,
haloprogin, hetacillin, hetacillin potassium, hexedine,
ibafloxacin, imipenem, isoconazole, isepamicin, isoniazid,
josamycin, kanamycin sulfate, kitasamycin, levofuraltadone,
levopropylcillin potassium, lexithromycin, lincomycin, lincomycin
hydrochloride, lomefloxacin, lomefloxacin hydrochloride,
lomefloxacin mesylate, loracarbef, mafenide, meclocycline,
meclocycline sulfosalicylate, megalomicin potassium phosphate,
mequidox, meropenem, methacycline, methacycline hydrochloride,
methenamine, methenamine hippurate, methenamine mandelate,
methicillin sodium, metioprim, metronidazole hydrochloride,
metronidazole phosphate, mezlocillin, mezlocillin sodium,
minocycline, minocycline hydrochloride, mirincamycin hydrochloride,
monensin, monensin sodiumr, nafcillin sodium, nalidixate sodium,
nalidixic acid, natainycin, nebramycin, neomycin palmitate,
neomycin sulfate, neomycin undecylenate, netilmicin sulfate,
neutramycin, nifuiradene, nifuraldezone, nifuratel, nifuratrone,
nifurdazil, nifurimide, nifiupirinol, nifurquinazol, nifurthiazole,
nitrocycline, nitrofurantoin, nitramide, norfloxacin, novobiocin
sodium, ofloxacin, onnetoprim, oxacillin sodium, oximonam, oximonam
sodium, oxolinic acid, oxytetracycline, oxytetracycline calcium,
oxytetracycline hydrochloride, paldimycin, parachlorophenol,
paulamycin, pefloxacin, pefloxacin mesylate, penamecillin, G
benzathine, pencillin G potassium, penicillin g procaine,
penicillin g sodium, penicillin V, penicillin V benzathine,
penicillin V hydrabamine, penicillin V potassium, pentizidone
sodium, phenyl aminosalicylate, piperacillin sodium, pirbenicillin
sodium, piridicillin sodium, pirlimycin hydrochloride,
pivampicillin hydrochloride, pivampicillin pamoate, pivampicillin
probenate, polymyxin B sulfate, porfiromycin, propikacin,
pyrazinamide, pyrithione zinc, quindecamine acetate, quinupristin,
racephenicol, ramoplanin, ranimycin, relomycin, repromicin,
rifabutin, rifametane, rifamexil, rifamide, rifampin, rifapentine,
rifaximin, rolitetracycline, rolitetracycline nitrate, rosaramicin,
rosaramicin butyrate, rosaramicin propionate, rosaramicin sodium
phosphate, rosaramicin stearate, rosoxacin, roxarsone,
roxithromycin, sancycline, sanfetrinem sodium, sarmoxicillin,
sarpicillin, scopafungin, sisomicin, sisomicin sulfate,
sparfloxacin, spectinomycin hydrochloride, spiramycin, stallimycin
hydrochloride, steffimycin, streptomycin sulfate, streptonicozid,
sulfabenz, sulfabenzamide, sulfacetamide, sulfacetamide sodium,
sulfacytine, sulfadiazine, sulfadiazine sodium, sulfadoxine,
sulfalene, sulfamerazine, sulfameter, sulfamethazine,
sulfamethizole, sulfamethoxazole, sulfamonomethoxine, sulfamoxole,
sulfanilate zinc, sulfanitran, sulfasalazine, sulfasomizole,
sulfathiazole, sulfazamet, sulfisoxazole, sulfisoxazole acetyl,
sulfisboxazole diolamine, sulfomyxin, sulopenem, sultamricillin,
suncillin sodium, talampicillin hydrochloride, teicoplanin,
temafloxacin hydrochloride, temocillin, tetracycline, tetracycline
hydrochloride, tetracycline phosphate complex, tetroxoprim,
thiamphenicol, thiphencillin potassium, ticarcillin cresyl sodium,
ticarcillin disodium, ticarcillin monosodium, ticlatone, tiodonium
chloride, tobramycin, tobramycin sulfate, tosufloxacin,
trimethoprim, trimethoprim sulfate, trisulfapyrimidines,
troleandomycin, trospectomycin sulfate, tyrothricin, vancomycin,
vancomycin hydrochloride, virginiamycin, and zorbamycin. Penicillin
G, which is used as an antibacterial agent for infections including
pneumonia, meningitis, and skin, bone, joint, stomach, blood, and
heart valve infections, is a particular example suitable for use
herein, tazobactum, sold under the trade names ZOSYN.TM. and
TAZOCIN.TM., ceftrioxone, sold under the trade name ROCEPHIN.TM.,
and metronidazol, sold under the trade name FLAGYL.TM., are also
used to treat bacterial infections and are further examples of
suitable compounds that can be used to prepare the disclosed ionic
liquids.
[0347] These and other suitable antibacterials can be identified
based on the desired properties of the antibacterial and whether
the antibacterial active is or can be converted into an ion. As
noted, identification of whether an antibacterial active is an ion
or can be converted into an ion can be done by a skilled artisan
inspecting the chemical structure of the antibacterial.
Specific Examples of Antiviral
[0348] When antiviral activity is a desired property of the
disclosed ionic liquids, one or more of the ions in the disclosed
ionic liquids can be an antiviral. Examples of suitable antiviral
actives include, but are not limited to, acemannan, acyclovir,
acyclovir sodium, adefovir, alovudine, alvircept sudotox,
amantadine hydrochloride, aranotin, arildone, atevirdine mesylate,
pyridine, cidofovir, cipamfylline, cytarabine hydrochloride,
delavirdine mesylate, desciclovir, didanosine, disoxaril,
edoxudine, enviradene, enviroxime, famciclovir, famotine
hydrochloride, fiacitabine, fialuridine, fosarilate, foscarnet
sodium, fosfonet sodium, ganciclovir, ganciclovir sodium,
idoxuridine, kethoxal, lamivudine, lobucavir, memotine
hydrochloride, methisazone, nevirapine, penciclovir, pirodavir,
ribavirin, rimantadine hydrochloride, saquinavir mesylate,
somantadine hydrochloride, sorivudine, statolon, stavudine,
tilorone hydrochloride, trifluridine, valacyclovir hydrochloride,
vidarabine, vidarabine phosphate, vidarabine sodium phosphate,
viroxime, zalcitabine, zidovudine, zinviroxime, and Tamiflu.
[0349] These and other suitable antivirals can be identified based
on the desired properties of the antiviral and whether the
antiviral is or can be converted into an ion. As noted,
identification of whether an antiviral is an ion or can be
converted into an ion can be done by a skilled artisan inspecting
the chemical structure of the antiviral.
Specific Examples of Pesticidal Actives
[0350] When pesticidal activity is a desired property of the
disclosed ionic liquids, one or more of the ions in the disclosed
ionic liquids can be a pesticide. Included within the meaning of
"pesticide" are insecticides and fungicides. Examples of suitable
pesticides include, but are not limited to, carfentrazone-ethyl,
sulfentrazone, clomazone, diciofop-methyl, oxamyl propargite,
prosulfuron, pyridate, pyriftalid, S-metolachlor, simazine,
terbuthylazine, terbutryn, triasulfuron, trifloxysulfuron,
trinexapac-ethyl, ametryn, atrazine, benoxacor, bifenthrin,
butafenacil, choline azide, chlortoluron, cinosulfuron, clodinafop,
cloquintocet, DEET, desmetryn, dicamba, dimethachlor,
dimethametryn, DTPA NaFe, EDDHA NaFe, fenclorim, flumetralin,
fluometuron, fluthiacetmethyl, halosulfuron, isoproturon,
metobromuron, metolachlor, norflurazon, oxasulfuron, piperophos,
pretilachlor, primisulfuron, prometryn, propaquizafop,
acibenzolar-s-methyl, chlorothalonil, cyproconazole, cyprodinil,
difenoconazole, fenpropidin, fenpropimorph, furalaxyl, metalaxyl,
metalaxyl-m, oxadixyl, penconazole, propiconazole, pyrifenox,
thiabendazol, abamectin, bromopropylate, cypermethrin, cypermethrin
high-cis, cyromazine, diafenthiuron, diazinon, dichlorvos,
disulfoton, emamectinbenzoate, fenoxycarb, formothion,
furathiocarb, lufenuron, methidathion, permethrine, codlemone,
phosphamidon, profenofos, pymetrozine, quinalphos, terrazole,
thiamethoxam, thiocyclam, thiometon, triallate, trifloxystrobin,
vinclozolin, zetacypermethrin, and the like. Prohexadione is a FDA
approved reduced risk fungicide and is also useful for the
disclosed ionic liquids. Further examples of suitable pesticides
can be found in The Pesticide Manual, 11.sup.th Edition, British
Crop Protection Council, 1997, which is incorporated by reference
herein at least for its teaching of pesticides.
[0351] These and other suitable pesticides can be identified based
on the desired properties of the pesticide and whether the
pesticide is or can be converted into an ion. As noted,
identification of whether a pesticide is an ion or can be converted
into an ion can be done by a skilled artisan inspecting the
chemical structure of the pesticide.
Specific Examples of Herbicidal Actives
[0352] When herbicidal activity is a desired property of the
disclosed ionic liquids, one or snore of the ions in the disclosed
ionic liquids can be a herbicide. Examples of suitable herbicides
include, bat are not limited to, carfentrazone, imazapyr, benefin,
acifluorfen, and
2-[2-chloro-3-(2,2,2-trifluoroethoxymethyl)-4-methylsulfonylbenzoyl]cyclo-
hexane-1.
[0353] Other suitable herbicides include inhibitors of the
biosynthesis of branched amino acids such as ethoxysulfuron,
flumetsulam, halosulfuron, imazamox, imazapyr, imazaquin,
imazethapyr, metosulam, nicosulfuron, primisulfuron, prosulfuron,
rimsulfuron, thifensulfuron-methyl, triflusulfuron,
N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-dimethylaminocarbonyl-5--
formylaminobenzenesulfonamide (Foramsulfuron), and the like. Still
further, suitable herbicides include inhibitors of the
photosynthesis electron transport such as ametryne, atrazine,
bromoxynil, cyanazine, diuron, hexazinone, metribuzin, pyridate,
terbuthylazine, and the like. In yet further examples, suitable
herbicides for the disclosed ionic liquids include synthetic auxins
such as copyralid, dicamba, diflufenzopyr, fluoroxypyr, and the
like. Inhibitors of fatty acid biosynthesis, such as butylate,
EPIC, fenoxaprop-P-ethyl, and the like, can also be used in the
disclosed ionic liquid compositions. In other examples, suitable
herbicides can include inhibitors of cell division such as
acetochlor, alachlor, dimethenamid, flufenacet, mefenacet,
metolachlor, 5-metolachlor, thenylchlor, and the like. In still
other examples, the herbicide can be an inhibitor of
protoporphyrinogen oxidase, such as fluthiacet-methyl,
carfentrazone-ethyl, and the like. Inhibitors of
hydroxyphenylpyruvate dioxygenase, such as isoxaflutole,
mesotrione, sulcotrione,
4-(4-trifluoromethyl-2-methylsulfonylbenzoyl)-5-hydroxy-1-methyl-3-methyl-
pyrazole, and the like, can also be used. Further examples of
suitable herbicides include, but are not limited to, glyphosate,
pendimethalin, asulam, triazifiam, diflufenican,
glufosinate-ammonium, and the like. Clofencet, fluoroxpyr,
mesosulfuron, diflufenzopyr are further examples of suitable
herbicides and they are FDA approved.
Specific Examples of Other Ions
[0354] In addition to the pharmaceutical, antibacterial, antiviral,
pesticidal, and herbicidal actives disclosed herein, other
compounds that are ions or can be converted to ions can be used in
the disclosed ionic liquid compositions. Specific examples of these
include, but are not limited to, the food additives Allura Red AC
(FD&C Red No. 40), Tartrazine (FD&C Yellow No. 5),
Indigotine (FD&C Blue No. 2), Erythrosine (FD&C Red No. 3),
and Sunset Yellow (FD&C Yellow No. 6), which are FDA-approved
color additives for food use. Further, nutraceuticals such as fatty
acids, cholesterols, vitamins, minerals, and trace elements can be
suitable ions for the disclosed ionic liquid compositions.
SEA-NIN-211 is an antifoulant that can be used as an ion id the
disclosed compositions.
Specific Examples of Energetics
[0355] The disclosed ionic liquid compositions can also include
high energy ingredients as well as explosive materials. The ability
to prepare a particular composition with high energy content
substituents (fuel) on one ion and high oxygen balance (oxidizers)
on the other ion opens wide applicability in today's high energy
compounds industry. The ability to independently form
differentially functionalized groups of ions, then chose two of
interest and combining them on demand to form desired strength
energetic material (Scheme 1) opens the doors for the quick
preparation of customizable energetic materials (e.g., explosives
with pre-designed power) and more safe storage technique of those
energetic materials since the components are separated before
usage. The disclosed compositions can be prepared according to one
of the following reaction protocols.
##STR00278##
where En is an energetic functional group containing either high
oxygen or nitrogen content (including but not limited to: nitro,
amino, cyano, widen, alkyl nitro, alkyl amino, alkyl cyano, alkyl
azido, alkoxy nitro, alkoxy amino, alkoxy cyano, and alkoxy azido),
IA.sup.- is an innocuous anion, IC+ is an innocuous cation, and
[IC][IA] is an easily removable and harmless byproduct from the
metathesis reaction. The reaction proceeds via ion exchange
reaction in solvent system media (solvent system is the solvent or
the mixture of the solvents in which at least one of the starting
materials dissolves). The solvents (or solvent) with substrates
dissolved in them separately are being combined, the byproduct is
being separated from the product (by solvent extraction or
precipitation) (Katritzky et al., "1-Butyl-3-methylimidazolium
3,5-dinitro-1,2,4-triazolate: a Novel IL Containing a Rigid, Planar
Energetic Anion," Chem Commun 868, 2005, which is incorporated by
reference herein).
[0356] Examples of those ionic liquid compositions include, hut are
not limited to, the mixture of at least two components of
functionalized 5- and 6-membered, and bicyclic fused ring
heterocyclic cations and anions containing 1, 2, 3, 4, or 5 atoms
of nitrogen in the ring structure, where all carbon and nitrogen
atoms in the ring structure can be functionalized with additional
substituents such as alkyl, allyl, aryl, nitro, nitrite, azido,
hydroxyl, carboxylic acid, ester, amide, amine, aldehyde, ketone,
epoxy, or functionalized alkyl and aryl groups (with any functional
mentioned above). Examples of such components (cations and/or
anions) are shown below.
##STR00279## ##STR00280##
where R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and
R.sup.7, are independent of one another, not present. H, alkenyl,
alkynyl, allyl, aryl, nitro, amino, cyano, azido, alkyl nitro,
alkyl amino, alkyl cyano, alkyl azido, alkoxy nitro, alkoxy amino,
alkoxy cyano, and alkoxy azido, nitrile, isonitrile, carboxylic
acid, ester, ether, CO.sub.2NR.sup.8.sub.2, CO.sub.2NHR.sup.8,
CO.sub.2NH.sub.2, amine, NHR.sup.8, NR.sup.8.sub.2, ketone,
aldehyde, or epoxy, wherein R.sup.8 is H, alkyl, alkenyl, alkynyl,
allyl, aryl, carboxylic acid, ester, ether, ketone, or
aldehyde.
##STR00281##
[0357] Utilizing this protocol, model compounds (4), which may
undergo further modification in terms of introduced functions (on
the cation precursor (1), anion precursors (2), and homologous
heterocycle core (both 1, and 2) (e.g., but not limited to:
imidazole, triazole, tetrazole, benzimidazole, and benztriazole
systems) can be formed.
[0358] The protocol for the formation of azolium azolate salts via
the reaction of two neutral components requires: zwitterionic
cation precursor (1) with carboxylate group appended on the
heterocycle core, and neutral heterocycle (2) with the pKa value
lower then that of carboxylate group in cation precursor (1). The
reaction can be carried in any solvent systems (pure solvent or
mixture of solvents) that allows for the dissolution of both
components, or without solvents at all. The reaction protocol
comprises the following steps:
[0359] Proton transfer reactions (protonation of carboxylate group
in zwitterionic cation precursor (1); (step i) which is
thermodynamically favored due to the difference in the pKa values
of the zwitterionic salt carboxylate group and azolate anion
(formed from deprotonation of anion precursor (2)).
[0360] Decarboxylation of the system containing the protonated
carboxylic acid group on the cation precursor in the intermediate
(cationic part of compound 3) (step ii). The decarboxyaltion may be
performed in the presence of either polar solvents (e.g., but not
limited to, DMSO, DMF, trialkylamine, H.sub.2O) or heat (temp
between 25.degree. C.-150.degree. C.). Additionally, the driving
force for this conversion is the production of gaseous CO.sub.2
which, upon removal from the reaction mixture, shifts the
thermodynamic equilibrium in favor of product formation.
[0361] Examples of those ionic liquid compositions made utilizing
above protocol include, but are not limited to, the mixture of at
least two components of functionalized 5-, 6-membered, and bicyclic
fused ring heterocyclic cation precursors and anion precursors
containing 1, 2, 3, 4, or 5 atoms of nitrogen in the ring
structure.
[0362] The cation precursors are neutral, zwitterionic species
(neutral molecule that within itself contains both: cation and
anion species) containing at least one cationic site (e.g., but not
limited to, protonated alkylated nitrogen atom) and one anionic
site (carboxylate (COO--) group). In the cation precursors all
carbon and nitrogen atoms in the ring structure can be
functionalized with additional substituents such as alkyl, allyl,
aryl, nitro, nitrile, azido, hydroxyl, carboxylic acid, ester,
amide, amine, aldehyde, ketone, epoxy, or functionalized alkyl and
aryl groups (with any functional mentioned above).
[0363] The anion precursors are neutral, substituted, or not
substituted, heterocyclic species containing at least one acidic
proton site on any of the nitrogen atoms. This hydrogen atom will
be utilized for the proton transfer reaction and consecutive
decarboxylation reaction to form final azolium azolate product (4)
as described in the protocol above. In the anion precursors all
carbon and nitrogen atoms in the ring structure can be
functionalized with additional substituents such as alkyl, allyl,
aryl, nitro, nitrile, azido, hydroxyl, carboxylic acid, ester,
amide, amine, aldehyde, ketone, epoxy, or functionalized alkyl and
aryl groups (with any functional mentioned above).
[0364] Examples of such components (cation precursors and/or anion
precursors) are shown below.
##STR00282## ##STR00283##
where for the cation precursor: at least one of the R.sup.1-R.sup.9
substituent groups (only among the ones directly appended to carbon
in heterocyclic ring) can be a carboxylate anion group. The
remaining groups can be, independent of one another, not present,
H, alkyl, alkenyl, alkynyl, allyl, aryl, nitro, amino, cyano,
azido, alkyl nitro, alkyl amino, alkyl cyano, alkyl azido, alkoxy
nitro, alkoxy amino, alkoxy cyano, and alkoxy azido, isonitrile,
carboxylic acid, ester, ether, CO.sub.2NR.sup.8.sub.2,
CO.sub.2NHR.sup.8, CO.sub.2NH.sub.2, amine, NHR.sup.8,
NR.sup.8.sub.2, ketone, aldehyde, or epoxy, wherein R.sup.8 is H,
alkyl, alkenyl, alkynyl, allyl, aryl, carboxylic acid, ester,
ether, ketone, or aldehyde.
[0365] And, where for the anion precursor: at least one of the
R.sup.1-R.sup.9 substituent groups (only among the once directly
appended to nitrogen in heterocyclic ring) can be an H atom
suitable for deprotonation to form stable heterocyclic azolate
anion. The remaining groups can be, independent of one another, not
present, H, alkenyl, alkynyl, allyl, aryl, nitro, amino, cyano,
azido, alkyl nitro, alkyl amino, alkyl cyano, alkyl azido, alkoxy
nitro, alkoxy amino, alkoxy cyano, and alkoxy azido, isonitrile,
carboxylic acid, ester, ether, CO2NR.sup.8.sub.2,
CO.sub.2NHR.sup.8, CO.sub.2NH.sub.2, amine, NHR.sup.8,
NR.sup.8.sub.2, ketone, aldehyde, or epoxy, wherein R.sup.8 is H,
alkyl, alkenyl, alkynyl, allyl, aryl, carboxylic acid, ester,
ether, ketone, or aldehyde.
[0366] Specific Ionic Liquids
[0367] Because the disclosed ionic liquid compositions can have
multiple functionalities or properties, each arising from the
various ions that make up the ionic liquid, the disclosed ionic
liquid compositions can be custom designed for numerous uses. As
disclosed herein, any combination of cations and anions, as
disclosed herein, can be made as long as the combination results in
an ionic liquid as described herein. That is, any compound or
active disclosed herein that has a given charge or can be made to
have a given charge (the "first ion(s)") can be combined with any
other compound or active disclosed herein having a charge opposite
to that of the first ion(s) or any compound that can be made to
have a charge opposite to that of the first ion(s). Thus, in many
examples, the ionic liquid compositions can have one type of cation
and one type of anion, in a 1:1 relationship, so that the net
charge of the ionic liquid is zero.
[0368] Furthermore, many of the ions disclosed herein can have
multiple charges. Thus, when one ion having a multiple charge is
used, more counterion(s) is needed, which will affect the ratio of
the two ions. For example, if a cation having a plus 2 charge is
used, then twice as much anion having a minus 1 charge is needed.
If a cation having a plus 3 charge is used, then three times as
much anion having a minus 1 charge is needed, and so on. While the
particular ratio of ions will depend on the type of ion and their
respective charges, the disclosed ionic liquids can have a cation
to anion ratio of 1:1:, 2:1, 3:1, 4:1, 1:3, 2:1, 3:2, 2:3, and the
like.
[0369] Many of the ionic liquid compositions disclosed herein can
also have more than one different kind of cation and/or more than
one different kind of anion. The use of more than one kind of
cation and/or anion can be particularly beneficial when one
prepares an ionic liquid composition comprising two or more
bioactive ions that are not desired to be in a 1:1 relationship. In
other words, according to the disclosed methods, ionic liquid
compositions that contain varying effective amounts (or doses) of
active substances can be prepared by varying the ratios of ions in
the composition, as long as the total amount of cations is balanced
by the total amount of anions. For example, an ionic liquid
composition disclosed herein can contain one type of cation with a
given property and two different anions (e.g., a first and second
anion), each with another different property. The resulting ionic
liquid in this example will be 1 part cation, 0.5 part first anion,
and 0.5 part second anion. Another example of this adjustment in
ion amounts can arise when one ion is particularly potent and thus
dilution is desired. For example, first cation that is particularly
potent can be combined with a second (or third, forth, etc.) cation
that is inert or has so other property that is desired. When these
cations are combined with one or more kinds of anions to form an
ionic liquid, the amount of the first cation is diluted by the
other the cation(s). As will be appreciated, many other such
variations in the amount of cations and anions can be present in
the disclosed methods and compositions. Thus, while specific ionic
liquid compositions having particular combinations of cations and
anions are disclosed herein, it is understood that the ratio of the
particular ions can be varied or adjusted by adding other ions, so
long as there is a balance of charge and the final composition is
an ionic liquid.
[0370] When the disclosed ionic liquid compositions have two or
more ions with a bioactive property (e.g., pharmaceutical active
ingredients, pesticidal actives, herbicidal actives, and the like),
these compositions can be particularly desired because each of the
active ingredients in the composition would have the same
solubility and would dissolve together when formulated or
administered. This can be particularly useful when overcoming
formulation, solubility, bioavailability, size, and polymorphism
issues. Further, when exact dosages of an active ingredient are
needed, the active ingredient as an ion can be combined with a
counterion that is innocuous or GRAS (generally recognized as
safe). As noted above, for example, if one active ingredient
(cation) is needed at half the dosage of another active ingredient
(anion), then an innocuous cation could be used as filler to
balance the charges. This same concept applies if more cation is
needed than anion.
[0371] A few specific examples of ionic liquid compositions
prepared from combinations of quaternary ammonium compounds and
saccharinates or acesulfamates have been demonstrated. Burgard
disclosed a process for preparing hexadecylpyridinium acesulfamate
and its use in the oral hygiene sector (Eur Pat Appl 2003-1270580
A1; US Pat Appl 2003-023084 A1). Hydrophilic quaternary ammonium
sacchrinates and acesulfamates and hydrophobic phosphonium
acesulfamates have been recently published (Carter et al., Chem
Comm, 2004, 630-631; Pernak et al., Eur J Org Chem, 2005, 650-652).
Saccharin, acting as a weak acid, can form salts with basic active
pharmaceutical ingredients including tertiary amines to form
quaternary nitrogen atoms (Bhatt et al., Chem Comm, 2005,
1073-1075). Also known in the literature is N-hexadecylpyridinium
saccharinate (CAS No. 7428-34-4).
[0372] Some other specific examples of the disclosed ionic liquids
include, but are not limited to, ionic liquids where any of the
cations in the ionic liquid are aliphatic benzylalkyl ammonium
cations (e.g., benzalkonium), dialiphatic dialkyl ammonium cations
(e.g., didecyldimethylammonium), and aliphatic heteroaryl cations
(e.g., hexadecylpyridinium) are combined with any of the anions of
sulfacetamide, ibuprofen, and saccharinate.
[0373] Benzalkonium (BA) is used chiefly as an antiseptic and
disinfectant. It is found in many over the counter and prescription
eye products, disinfectants, shampoos, and deodorants, it also acts
as a preservative in many pharmaceutical preparations.
Didecyldimethylammonium (DDA) is used as an antiseptic and
surfactant. N-hexadecylpyridinium (HEX) is used as an antiseptic
agent alone or in combination with other drugs for oral and throat
care, HEX is essentially nontoxic and can be applied to the skin or
mucous membranes.
[0374] Sulfacetamide is used to control antibacterial activity and
is sold under the trade name KLARON.TM. in the treatment of acne.
Ibuprofen is used as an anti-inflammatory and pain reliever.
Saccharinate is used as a sweetener.
[0375] Some specific examples of suitable ionic liquids include,
but are not limited to, benzalkonium sulfacetamide
(BA-sulfacetamide), didecyldimethylammonium sulfacetamide
(DDA-sulfacetamide), N-hexadecylpyridinium sulfacetamide
(HEX-sulfacetamide), benzalkonium ibuprofen (BA-ibuprofen),
didecyldimethylammonium ibuprofen (DDA-ibuprofen),
N-hexadecylpyridinium ibuprofen (HEX-ibuprofen), and benzalkonium
acesulfamate, didecyldimethylammonium acesulfamate,
N-hexadecylpyridinium acesulfamate, and benzalkonium saccharinate
(BA-SAC).
[0376] In other examples, an ion that is antiseptic can be combined
with an ion that is antibacterial agent. For example, an ionic
liquid can comprise benzalkonium and sulfacetamide, which is shown
in formula X.
##STR00284##
Another example is the combination of didecyldimethylammonium
sulfacetamide, which is shown in formula XI.
##STR00285##
Still another example is the combination of N-hexadecylpyridinium
sulfacetamide, which is shown in formula XII.
##STR00286##
Such antiseptic/antibacterial compositions can be used in the
treatment of wounds, for example, wounds near the scalp where a
composition with both disinfectant and antibacterial properties is
desirable. Such compounds could also be used for skin care, e.g.,
to treat acne.
[0377] In still further examples, an ion that is antibacterial can
be combined with an anti-inflammatory and/or pain reliever. Such
compositions can be used as a disinfectant and for pain relief. For
example, an ionic liquid can comprise benzalkonium and ibuprofen,
which is shown in formula XIII.
##STR00287##
Also, the ionic liquid composition can comprise
didecyldimethylammonium and ibuprofen, which is shown in formula
XIV.
##STR00288##
Further, the ionic liquid composition can comprise
N-hexadecylpyridinium and ibuprofen, which is shown in formula
XV.
##STR00289##
[0378] In other examples of ionic liquid compositions disclosed
herein, an ion that is an antibacterial can be combined with an ion
that is a sweetener. Such compositions can be used to improve the
taste of medicines and hygiene products and can be used in, for
example, toothpaste, and children's medicine. Some specific
examples of such ionic liquids is prepared by combining the
antibacterial agents benzalkonium, didecyldimethylammonium, or
N-hexadecyl)pyridinium and the sweetener acesulfamate, as shown in
formulas XVI, XVII, and XVIII, respectively.
##STR00290##
The antibacterial agents benzalkonium, didecyldimethylammonium, and
N-hexadecylpyridinium can also be combined with the sweetener
saccharinate, as shown in formulas XIV, XX, and XXI,
respectively.
##STR00291##
[0379] In still other examples, the ionic liquid composition can
comprise an ion that is an antibacterial agent with an ion that is
a UV-blocker, such as trans-cinnamate. Such compositions can be
used as disinfectants and for protection against UV radiation, as
would be desirable for treating wounds exposed to the Sun's
radiation. Specific examples of such composition include, hut are
not limited to, compositions where the cation is an antibacterial
agent such as benzalkonium, didecyldimethylammonium, or
N-hexadecylpyridinium, and the anion is trans-cinnamate, as is
shown in formulas XXII, XXIII, and XXIV respectively.
##STR00292##
[0380] In still other examples, the disclosed ionic liquids can
comprise an ion that is an antibacterial and an ion that can
provide wetting and controls reaction rate, particle size,
viscosity, polymer molecular weight, and stability in emulsion
polymerization systems, e.g., sodium dihexylsulfosuccinate Colawet
MA-80 from Colonial Chemicals, South Pittsburg, Tenn.)). Specific
examples of such compositions include, but are not limited to,
compositions where the cation is an antibacterial agent such as
benzalkonium, didecyldimethylammonium, or n-hexadecylpyridinium,
and the anion is Colawet MA-80, as shown in formulas XXV, XXVI, and
XXVII, respectively.
##STR00293##
[0381] In further examples, the disclosed ionic liquid compositions
can comprise an ion that is antibacterial and an ion that is a food
colorant. Examples of such ionic liquid compositions include, but
are not limited to, compositions where the cation is an
antibacterial agent such as benzalkonium, didecyldimethylammonium,
or N-hexadecylpyridinium, and the anion is Fast Green FCF, an FDA
approved color additive that provides a sea green hue and is used
in products such as beverages, puddings, ice cream, sherbet,
cherries, confections, baked goods, and dairy products. Other food
coloring anions, which are well known in the art, can be used as
well.
##STR00294##
[0382] In still further examples, the disclosed ionic liquid
compositions can comprise a cation that is an antibacterial and an
anion that is an antibacterial. For example, the cationic
antibacterial agents disclosed herein can be combined with the
anionic piperacillin, which is an extended-spectrum penicillin.
Piperacillin is primarily used in the treatment of susceptible
infections such as septicemia, acute and chronic respiratory tract
infections, skin and soft tissue infections, and urinary tract
infections.
##STR00295##
[0383] Still further specific examples of the disclosed ionic
liquid compositions are those where the anion is benzoate and the
cation comprises one or more of
(2-acetoxyethyl)-dodecyloxymethyldimethylammonium,
(2-acetoxyethyl)-heptyloxymethyldimethylammonium,
(2-hydroxyethyl)-cyclododecyloxymethyldimethylammonium,
(2-hydroxyethyl)-dimethylundecyloxymethylammonium.
[0384] Other examples of the disclosed ionic liquid compositions
are those where the cation comprises benzalkonium,
didecyldimethylammonium, or N-hexadecylpyridinium and the anion
comprises one or more of acesulfamate, benzoate, colawet ma-80,
fast green FCF, ibuprofen, penicillin G, piperacillin,
saccharinate, salicylate, salicylate, sulfacetamide,
trans-cinnamate, sulfathiazole, thimerosal, valproic acid,
mepenzolate, docusate. In three specific examples, benzalkonium is
combined with mepenzolate and docusate in a 1:1:2 ratio, a 2:1:3
ratio, or a 1:2:3 ration. In another example, benzalkonium is
combined with sulfathiazole and saccharinate in a 2:1:1 ratio.
[0385] Further specific examples of the disclosed ionic liquid
compositions are those where the cation is didecyldimethylammonium
and the anion comprises one or more of saccharinate,
(S)-6-methoxy-.-methyl-2-naphthaleneacetate,
2-[(2,6-dichlorophenyl)amino]-benzeneacetate,
2-[2,6-dichlorophenyl)amino]-benzeneacetate, 2-acetoxybenzoate,
acesulfamate, benzoate, colawet ma-80, fast green FCF, ibuprofen,
mandelate,
N-[4-[[(2-amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-L-gl-
utamate, nicotinate, penicillin G, piperacillin,
p-toluenesulfonate, salicylate, sulfacetamide, or
trans-cinnamate.
[0386] Other specific examples of the disclosed ionic liquid
compositions are those where the cation is hexadecylpyridinium and
the anion comprises one or more of colawet ma-80, fast green FCF,
penicillin G, piperacillin, or sulfacetamide.
[0387] Still further specific examples of the disclosed ionic
liquid compositions are those where the cation is
hexadecylpyridinium and the anion comprises one or more of
clofencet, fluoroxypyr, diflufenzopyr, mesosulfuron, prohexadione,
pantoprazole, risedronate, losartan, rabeprazole, fosinopril,
ceftioxone, atorvastatin, pravastatin, alendronate, montelukast,
tazobactam, Allura Red AC, tartrazine, indigotine, erythrosine, or
Sunset Yellow.
[0388] Further specific examples of the disclosed ionic liquid
compositions are those where the cation is didecyldimethylammonium
and the anion comprises one or more of clofencet, fluoroxypyr,
diflufenzopyr, mesosulfuron, prohexadione, pantoprazole,
risedronate, losartan, rabeprazole, fosinopril, ceftioxone,
atorvastatin, pravastatin, alendronate, montelukast, tazobactam,
Allura Red AC, tartrazine, indigotine, erythrosine, or Sunset
Yellow.
[0389] Other specific examples of the disclosed ionic liquid
compositions are those where the cation is benzalkonium and the
anion comprises one or more of clofencet, fluoroxypyr,
diflufenzopyr, mesosulfuron, prohexadione, pantoprazole,
risedronate, losartan, rabeprazole, fosinopril, ceftioxone,
atorvastatin, pravastatin, alendronate, montelukast, tazobactam,
Allura Red AC, tartrazine, indigotine, erythrosine, or Sunset
Yellow.
[0390] Still further examples include the compositions docusate
lidocaine, miconazole/econazole docusate, streptomycin docusate,
and isoniazide docusate. Docusate combined with any of the cationic
5 and 6 membered quaternary ammonium ring compounds disclosed
herein are also contemplated herein.
[0391] Still further examples include a cation that is an
anticholinergic like mepenzolate and the anion is docusate.
[0392] Another example comprises itraconazole, which inhibits
cytochrome p540 oxidase mediated synthesis of ergosterol,
itraconazole is a 1:1:1 racemic mixture of four diastereomers
comprising 2 enantiomeric pairs. Generally, it has poor adsorption
especially when givenin capsule form. This is though to occur
because 99.8% of the drug becomes bound to proteins in the body, it
has been shown that absorption is improved with acid as the pKa is
3.70; therefore, it is recommended that this drug be taken with
orange juice. The compound is insoluble in water, slightly soluble
in alcohol, and freely soluble in dichloromethane. This compound
can be combined with any of the anions disclosed herein, for
example, sulfacetamide, colawet MA-80, and docusate.
[0393] Also contemplated are ionic liquids that are prodrugs. A
prodrug is a pharmacologically inactive compound that is converted
to an active drug by a metabolic biotransformation. Prodrugs are
used when there are concerns regarding a drugs solubility,
absorption and distribution, she specificity, stability, prolonged
release, toxicity, patient acceptability, and formulation concerns.
Carrier linked prodrugs are also contemplated. A carrier linked
prodrug is a compound that contains an active drug linked to a
carrier group that can be removed enzymatically, such as an ester,
which is hydrolyzed to an active carboxylicacid containing drug.
Other types of carrier linkages include alcohols and carboxylic
acids, amines, and carbonyl compounds. Also contemplated are mutual
prodrugs, which comprise two drugs attached to each other where one
is the carrier for the other and vice versa.
[0394] Still further examples include compositions comprising
lidocaine and silver. This composition has a component that is
functional for topical anesthesia (lidocaine) with one Ag+ that has
antimicrobial properties. This can be used in conjunction with
lidocaine docusate, as described herein, to create ointments or
bandage materials that are capable of providing a palliative effect
as well as suppression of microorganism growth. Similarly, silver
docusate can be prepared, which can provide a lipophilic salt of
silver that would be soluble in lidocaine docusate, other ILs, or
even non-IL creme bases, for end-use as a topical antimicrobial
agent.
[0395] Still further examples include compositions comprising
ranitidine and docusate. This compound can generate a rather
lipophilic, hydrophobic version of ranitidine, which would be both
non-crystalline and sufficiently sluggish in its rate of
dissolution against biofluids that it could serve as a slow-release
form of the drug. Lidocain docusate is another example contemplated
herein.
Methods
[0396] The disclosed ionic liquid compositions can be prepared by
combining one or more kinds of cations or cation precursors with
one or more kinds of anions or anion precursor. Providing of the
particular ions is largely based on the identifying desired
properties of the ion (e.g., its charge and whether it has a
particular bioactivity that is desired to be present in the
resulting ionic liquid). Methods of identifying suitable ions are
disclosed herein, for example, by considering the chemical
structure and charge of the compounds and whether the ion
combination will produce an ionic liquid.
[0397] Typically, when preparing an ionic liquid composition as
disclosed herein, an ion that minimizes coulombic interactions by
diffusing its charge over several atoms in the ion is identified.
An example of this is the alkylheteroaryl cations disclosed herein
where the positive charge is spread over the atoms of the
heteroaryl ring. Then a weakly coordinating counterion, which also
delocalizes charge over several atoms, is chosen. In general,
more-complex and higher molecular weight cations and anions have a
greater number of intermolecular contacts, which serves to raise
melting point and increase the viscosity of the ionic liquid
composition.
[0398] Further, when preparing an ionic liquid composition as
disclosed herein, molecular asymmetry can be particularly desired.
Low-symmetry cations and anions typically reduce packing efficiency
in the crystalline state and lower melting points.
[0399] It is also desirable that the cation should not be more
nucleophilic than the neutral form of the cation. If this is the
case, then suitable anions can be selected by considering their
pKa. For example, by utilizing the pKa of acid functionalized
compounds and the pKb of base functionalized compounds, one can
combine the neutral species of acids and bases into one neutral
compound possessing the functions of both compounds. To
successfully produce an ionic liquid by this method, the pKa or pKb
of compound A should be different by approximately 5 orders of
magnitude from the pKa or pKb of compound B. This insures that the
acidity or basicity at that hydrogen is sufficient to remove or add
a hydrogen at that position. This will then produce an anion on the
acidic compound and a cation on the basic compound.
[0400] One method for identifying a suitable ion combination for
preparing an ionic liquid as disclosed herein is by computer
program. It is also possible to use a computer to select various
cation and anion combinations. For example, the program called
ERWIN.TM., sold by Computer Associates (Islandia, N.Y.), can be
used. This computer program is comprised of two models: a forward
model which predicts the melting points and drug delivery rates of
a formulation of ionic liquids, and a backwards model will allow
the user to select which type of pharmaceutical agents that are
desired along with liquid range and delivery rates and the program
will give all the formulations which meet these criterion.
[0401] FIG. 3 illustrates how the two models interact. CODESSA.TM.
(Semichem, Inc. Shawnee Mission, KS) can be used to calculate the
descriptors that can be used to construe the forward model. For
example, if a researcher desires a formulation to have
antibacterial and painkilling therapeutic agents as well as the
formulation to exist as a liquid at room temperature and have a
delivery rate of 1 gram absorbed per minute, the researcher would
feed this request into the program and all of the formulations
meeting these requirements and being composed entirely of a
balanced ionic liquid formula would be suggested to the
researcher.
[0402] Once the desired ions are provided, the ions can be combined
to form the disclosed ionic liquids. There are generally two
methods for preparing an ionic liquid: (I) metathesis of a salt of
the desired cation (e.g., a halide salt) with a salt of the desired
anion (e.g., transition metal, like Ag, salt, Group I or II metal
salt, or ammonium salt). Such reactions can be performed with many
different types of salts; and (2) an acid-base neutralization
reaction. Another method for forming the disclosed ionic liquid
compostions involves a reaction between a salt of a desired cation,
say CationX where X is an appropriate balancing anion (including
but not necessarily a halide), and an acid to yield the ionic
liquid and FIX byproduct. Conversely, the disclosed ionic liquid
compositions can be formed by reacting a salt of a desired anion,
say YAnion where Y is an appropriate balancing cation, with a base
to yield the ionic liquid and Ybase byproduct.
[0403] Many of the bioactive compounds (e.g., pharmaceutical
actives, pesticidal actives, herbicidal actives, etc.) and
energetic compounds disclosed herein are cationic or can be made
cationic, the identification of which can be made by simple
inspection of the chemical structure as disclosed herein. Further,
many of these compounds are commercially available as their halide
salts or can be converted to their halide salts by reactions with
acids (e.g., HF, HCl, HBr, or HI) or by treating a halogenated
compound with a nucleophile such as an amine. Further many of the
anions disclosed herein are commercially available as metal salts,
Group I or metal salts, or ammonium salts. Combining such cations
and anions in a solvent with optional heating can thus produce the
ionic liquid compositions. For a review of the synthesis of ionic
liquids see, for example, Welton, Chem Rev 1999, 99:2071-2083,
which is incorporated by reference herein for at least its
teachings of ionic liquid synthesis.
[0404] Ionic liquids which are immiscible with water are often
conveniently prepared by the combination of aqueous solutions of
two precursor salts, each of which contains one of the two
requisite ions of the targeted ionic liquids. On combination, the
desired salt forms a separate phase from the aqueous admixture.
Such phases are readily washed free of byproduct salts with
additional water, and may subsequently subjected to other
procedures (e.g., as disclosed in the Examples) to separate them
from non-water soluble impurities. In certain cases, it is also
possible to prepare water immiscible ionic liquids by the addition
to a neutral amine-containing compound (e.g., an active
pharmaceutical ingredient) of an acid such as aqueous HTf.sub.2N.
Certain Tf.sub.2N.sup.- salts of N--H containing cations are known
to be water-immiscible.
[0405] The purification of ionic liquids can be accomplished by
techniques familiar to those skilled in the art of organic and
inorganic synthesis, with the notable exception of purification by
distillation of the ionic liquid. One particularly useful approach
is the use of conventional or reverse-phase chromatography to
separate the salt of interest from other ionic or non-ionic
materials, followed by the separation of the ionic liquid from the
eluting solvent, commonly by evaporation of the latter. In some
cases, ionic liquids can be purified by crystallization or thermal
zone crystallization at appropriate conditions of temperature and
pressure. Such techniques can include the use of a solvent from
which the ionic liquid can be crystallized at an appropriate
temperature. Other purification techniques include exchange column
chromatography and supercritical CO.sub.2 fluid extraction.
Uses
[0406] The disclosed ionic liquid compositions have many uses. For
example, the disclosed ionic liquid compositions can be used to
allow fine tuning and control of the rate of dissolution,
solubility, and bioavailability, to allow control over physical
properties and mechanical strength, to improve homogenous dosing,
and to allow easier formulations. The disclosed ionic liquid
compositions also make having compositions with additional
functionality possible.
[0407] One notable advantage of the disclosed ionic liquid
compositions is that they can be used to alleviate the problems
associated with polymorphism. For example, a compound subject to
polymorphism can be used as an ion in the disclosed ionic liquid
compositions. In this way, the compound will become part of the
ionic liquid composition and thus not a crystalline solid that is
subject to polymorphism. Alternatively, polymorphism can be
prevented by dissolving the compound in the ionic liquid. An
advantage of having ionic liquid compositions is that the
solubility and bioavailability can be known and predicted. This
allows homogeneous and predictable dosing and tableting.
[0408] Another notable advantage is that the disclosed ionic liquid
compositions can be used to alleviate side effects associated with
various compounds. For example, the disclosed ionic liquid
compositions can contain an ion from a drug known to have an
undesirable side effect along with a counterion that is a drug
known to alleviate or counteract that side effect. An example of
this is an ionic liquid composition that comprises the ions of
morphine and docusate. Such a composition can be used to treat pain
due to the presence of morphine and relieve constipation due to the
presence of docusate. Along the same lines, many pharmaceuticals
are known to cause constipation, and ionic liquids of these
compounds with docusate or other laxatives are contemplated
herein.
[0409] Generally, any use that exists for one or more of the ionic
components in the ionic liquid is also a use for the ionic liquid
composition itself. For example, if one of the ions in an ionic
liquid composition disclosed herein is a pharmaceutical active,
then the ionic liquid composition can also be used for the same
indication as the pharmaceutical active. In fact, many of the
compounds disclosed herein as being suitable ions for the disclosed
ionic liquids have already been proven to be effective alone or in
some other preparation. Many of the disclosed compounds are even
FDA approved. When such compounds are prepared as part of an ionic
liquid, as disclosed herein, they can still maintain their
efficacy, and can even have their efficacy enhanced by being part
of the ionic liquid composition. For example, when an ionic liquid
having a pharmaceutical active as one or more of its cations or
anions is administered to a subject, the pharmaceutical active will
dissociate from the ionic liquid and be available to the subject in
the same way as had a solid form (e.g., tablet) or solution of the
pharmaceutical active been administered. This effect is also
observed for the antibacterial, antiviral, pesticidal, herbicidal,
nutritional, food additives and other compounds and actives
disclosed herein.
[0410] Other uses of the disclosed ionic liquid compositions
include the dissolution of the ionic liquid into liquid bandages.
Liquid bandages are available from commercial suppliers such as
Johnson and Johnson. By dissolving the disclosed ionic liquid
compositions into a liquid bandage, the various ions in the ionic
liquid (e.g., antiinfective, steroidal, anesthetic, etc. ions) can
be released into a wound and provide beneficial effects.
[0411] Further, the disclosed ionic liquids can be coated onto a
cellulosic bandage (e.g., a gauze or dressing). Thus, by soaking,
spraying, or otherwise contacting a bandage with the disclosed
ionic liquid compositions, the bandage will contain the various
active ions of the ionic liquid along with their associated
functionality. In this regard, it may be desirable to use an ionic
liquid composition that melts at or around body temperature. In
this way, the ionic liquid composition can "leach" out of the
bandage and onto the site contacted by the bandage.
[0412] Additionally, the disclosed ionic liquids can be melted by a
consumer or physician (e.g., with hot water) and then "painted"
onto an area of interest. It would then cool as a thin, solid
coating of the ionic liquid. This use can provide a slow release
form of the API in the ionic liquid or impart a desirable barrier
on the area of interest.
[0413] Depending on the particular ions, the disclosed ionic liquid
compositions can be used to treat a subject diagnosed with, for
example, endocrine disorders, diabetes, infertility, hormone
deficiencies, osteoporosis, ophthalmological disorders,
neurodegenerative disorders, Alzheimer's disease, dementia,
Parkinson's disease, multiple sclerosis, Huntington's disease,
cardiovascular disorders, atherosclerosis, hyper-coagulable states,
hypo-coagulable states, coronary disease, cerebrovascular events,
metabolic disorders, obesity, vitamin deficiencies, renal
disorders, renal failure, haematological disorders, anemia of
different entities, immunologic and rheumatologic disorders,
autoimmune diseases, immune deficiencies, infectious diseases,
viral infections, bacterial infections, fungal infections,
parasitic infections, neoplastic diseases, multi-factorial
disorders, impotence, chronic pain, depression, and different
fibrosis states.
[0414] Similarly, with herbicidal and pesticidal actives, the ionic
liquid compositions disclosed herein that contain ionic pesticidal
and herbicidal actives can be used in the same way as the actives
themselves. Thus, any use contemplated for a pesticidal and
herbicidal active is contemplated herein for an ionic liquid
composition containing that active.
[0415] Furthermore, because the disclosed ionic liquid compositions
are liquid at a given temperature, they avoid problems associated
with polymorphism. For example, one can vary the individual ions
and the combination of ions to fine tune the characteristics of the
compositions, thus obtaining a composition with desired properties
e.g., better dissolution, solubility, or bioavailability). This can
lead to easier dosing and formulating of the actives in the
compositions. By preparing and using the disclosed ionic liquid
compositions, one need not need to prepare, screen, and
characterize numerous crystalline forms of the actives.
[0416] In one aspect, disclosed herein are methods for using ionic
liquid compositions that comprise administering an effective amount
of at least one ionic liquid composition as disclosed herein. By
the term "effective amount" of a compound as provided herein is
meant a nontoxic but sufficient amount to provide the desired
result. As will be pointed out below, the exact amount required
will vary from subject to subject, depending on the species, age,
and general condition of the subject, the severity of the disease
that is being treated, the particular compound used, its mode of
administration, and the like. Thus, it is not possible to specify
an exact "effective amount," However, an appropriate effective
amount can be determined by one of ordinary skill in the art using
only routine experimentation. The dose, schedule of doses, and
route of administration can be varied.
[0417] The efficacy of administration of a particular dose of the
ionic liquid compositions according to the methods described herein
can be determined by evaluating the particular aspects of the
medical history, signs, symptoms, and objective laboratory tests
that are known to be useful in evaluating the status of a subject
in need of attention for the treatment of a disease and/or
condition. These signs, symptoms, and objective laboratory tests
will vary, depending upon the particular disease or condition being
treated or prevented, as will be known to any clinician who treats
such patients or a researcher conducting experimentation in this
field. For example, if, based on a comparison with an appropriate
control group and/or knowledge of the normal progression of the
disease in the general population or the particular individual: (1)
a subject's physical condition is shown to be improved, (2) the
progression of the disease or condition is shown to be stabilized,
or slowed, or reversed, or (3) the need for other medications for
treating the disease or condition is lessened or obviated, then a
particular treatment regimen will be considered efficacious.
[0418] Many of the disclosed ionic liquid compositions can be used
therapeutically as neat ionic liquids. Also, the disclosed ionic
liquids can be used in combination with a pharmaceutically
acceptable carrier. By "pharmaceutically acceptable" is meant a
material that is not biologically or otherwise undesirable, i.e.,
the material may be administered to a subject without causing any
undesirable biological effects or interacting in a deleterious
manner with any of the other components of the pharmaceutical
formulation in which it is contained. The carrier would naturally
be selected to any degradation of the active ingredient and to
minimize any adverse side effects in the subject, as would be well
known to one of skill in the art. In another aspect, many of the
disclosed ionic liquids can be used prophylactically, i.e., as a
preventative agent, either neat or with a pharmaceutically
acceptable carrier. The ionic liquid compositions disclosed herein
can be conveniently formulated into pharmaceutical compositions
composed of neat ionic liquid or in association with a
pharmaceutically acceptable carrier. See e.g., Remington's
Pharmaceutical Sciences, latest edition, by E. W. Martin Mack Pub.
Co., Easton, Pa., which discloses typical carriers and conventional
methods of preparing pharmaceutical compositions that can be used
in conjunction with the preparation of formulations of the
compounds described herein and which is incorporated by reference
herein. Such pharmaceutical carriers, most typically, would be
standard carriers for administration of compositions to humans and
non-humans, including solutions such as sterile water, saline, and
buffered solutions at physiological pH. Other compounds can be
administered according to standard procedures used by those skilled
in the art. For example, pharmaceutical compositions can also
include one or more additional active ingredients such as
antimicrobial agents, anti-inflammatory agents, anesthetics, and
the like.
[0419] Examples of pharmaceutically-acceptable carriers include,
but are not limited to, saline, Ringer's solution and dextrose
solution. The pH of the solution is preferably from about 5 to
about 8, and more preferably from about 7 to about 7.5. Further
carriers include sustained release preparations such as
semipermeable matrices of solid hydrophobic polymers containing the
disclosed compounds, which matrices are in the form of shaped
articles, e.g., films, liposomes, microparticles, or microcapsules,
it will be apparent to those persons skilled in the art that
certain carriers can be more preferable depending upon, for
instance, the route of administration and concentration of
composition being administered. Other compounds can be administered
according to standard procedures used by those skilled in the
art.
[0420] Pharmaceutical formulations can include additional carriers,
as well as thickeners, diluents, buffers, preservatives, surface
active agents and the like in addition to the compounds disclosed
herein. Pharmaceutical formulations can also include one or more
additional active ingredients such as antimicrobial agents,
anti-inflammatory agents, anesthetics, and the like.
[0421] The pharmaceutical formulation can be administered in a
number of ways depending on whether local or systemic treatment is
desired, and on the area to be treated. Administration may be
topically (including ophthalmically, vaginally, rectally,
intranasally), orally, by inhalation, or parenterally, for example
by intravenous drip, subcutaneous, intraperitoneal or intramuscular
injection. The disclosed compounds can be administered
intravenously, intraperitoneally, intramuscularly, subcutaneously,
intracavity, or transdermally as is described more fully elsewhere
herein.
[0422] Administration and Delivery
[0423] In one aspect, disclosed herein are uses of a delivery
device to deliver an ionic liquid composition as disclosed herein
to a subject. Further, disclosed are methods for delivering an
ionic liquid composition to a subject by administering to the
subject any of the nutritional supplements, pharmaceutical
formulations, controlled release vehicles, delivery and/or
devices.
[0424] The compositions described herein can be administered to the
subject in a number of ways depending on whether local or systemic
treatment is desired, and on the area to be treated. Thus, for
example, a composition described herein can be administered as an
ophthalmic solution and/or ointment to the surface of the eye.
Moreover, a compound or pharmaceutical composition can be
administered to a subject vaginally, rectally, intranasally,
orally, by inhalation, or parenterally, for example, by
intradermal, subcutaneous, intramuscular, intraperitoneal,
intrarectal, intraarterial, intralymphatic, intravenous,
intrathecal and intratracheal routes. Parenteral administration, if
used, is generally characterized by injection. Injectables can be
prepared in conventional forms, either as liquid solutions or
suspensions, solid forms suitable for solution or suspension in
liquid prior to injection, or as emulsions. A more recently revised
approach for parenteral administration involves use of a slow
release or sustained release system such that a constant dosage is
maintained. In one example an ionic liquid composition such as
lidocaine docusate is contacted to the skin of a subject to provide
an anesthetic effect.
[0425] Preparations for parenteral administration include sterile
aqueous or non-aqueous solutions, suspensions, and emulsions which
cart also contain buffers, diluents and other suitable additives.
Examples of non-aqueous solvents are propylene glycol, polyethylene
glycol, vegetable oils such as olive oil, and injectable organic
esters such as ethyl oleate. Aqueous carriers include water,
alcoholic/aqueous solutions, emulsions or suspensions, including
saline and buffered media. Parenteral vehicles include sodium
chloride solution, Ringer's dextrose, dextrose and sodium chloride,
lactated Ringer's, or fixed oils. Intravenous vehicles include
fluid and nutrient replenishers, electrolyte replenishers (such as
those based on Ringer's dextrose), and the like. Preservatives and
other additives, such as antimicrobials, anti-oxidants, chelating
agents, and inert gases and the like, can also be present.
[0426] Formulations for topical administration can include
ointments, lotions, creams, gels, drops, suppositories, sprays,
liquids and powders. The disclosed ionic liquid compositions having
hydrophobic ions can be particularly useful in such applications
because they can adhere to the surface longer when exposed to water
or other fluids than would a similar hydrophilic salt. Likewise,
ionic liquids comprising disinfectant, herbicide, or pesticide ions
and hydrophobic counterions can be expected to resist erosion from
rainfall. Conventional pharmaceutical carriers, aqueous, powder or
oily bases, thickeners and the like can be necessary or desirable.
When applied to skin or mucous tissues (e.g., oral applications)
ionic liquid compositions containing pharmaceutical actives
formulated with highly hydrophobic anions or cations (as
appropriate) can have longer durations of adhesion when exposed to
water or other fluids than would similar hydrophilic salts applied
in these environments. This would be particularly beneficial for
sun screens. It should also be noted that disinfectants,
pesticides, or herbicides applied to plant leaves can be less prone
to be lost by rain even if it follows application.
[0427] When one or more ions in the disclosed ionic liquid
compositions are an antibacterial, an effective amount of the
composition can be contacted (i.e., administered) to any surface
that has bacteria. Similarly, when one or more ions in the
disclosed ionic liquid composition are a pesticidal active, an
effective amount of the composition can be administered to an area
to control pests. When one or more ions in the disclosed ionic
liquid composition are a herbicidal active, an effective amount of
the composition can be administered to an area to control plants.
Techniques for contacting such surfaces and areas with the
disclosed ionic liquid compositions can include, spraying, coating,
dipping, immersing, or pouring the composition into or onto the
surface or area. The precise technique will depend on such factors
as the type and amount of infestation or contamination, the size of
the area, the amount of composition needed, preference, cost and
the like.
[0428] Delivery Devices
[0429] Any of the compounds described herein can be incorporated
into a delivery device. Examples of delivery devices include, but
are not limited to, microcapsules, microspheres, nanospheres or
nanoparticles, liposomes, noisome, nanoerythrosome, nanoparticles,
gels, gel capsules, tablets, lotions, creams, sprays, emulsions, or
powders. Other examples of delivery devices that are suitable for
non-oral administration include pulmospheres. Examples of
particular delivery devices useful herein are described below.
[0430] The disclosed compounds can be incorporated into liposomes.
As is known in the art, liposomes are generally derived from
phospholipids or other lipid substances. Liposomes are formed by
mono- or multi-lamellar hydrated liquid crystals that are dispersed
in an aqueous medium. Any non-toxic, physiologically acceptable and
metabolizable lipid capable of forming liposomes can be used. The
disclosed compositions in liposome form can contain, in addition to
a compound disclosed herein, stabilizers, preservatives,
excipients, and the like. Examples of suitable lipids are the
phospholipids and the phosphatidyl cholines (lecithins), both
natural and synthetic. Methods of forming, liposomes are known in
the art. See, e.g., Prescott, Ed., Methods in Cell Biology, Volume
XIV, Academic Press, New York, p. 33 et seq., 1976, which is hereby
incorporated by reference herein for its teachings of liposomes and
their preparation.
[0431] In other examples, the liposomes can be cationic liposomes
(e.g., DOTMA, DOPE, DC cholesterol) or anionic liposomes. Liposomes
can further comprise proteins to facilitate targeting a particular
cell, if desired. Administration of a composition comprising a
compound and a cationic liposome can be administered to the blood
afferent to a target organ or inhaled into the respiratory tract to
target cells of the respiratory tract. Regarding liposomes, see,
e.g., Brigham, et al., Am J Resp Cell Mol Biol 1:95-100, 1989;
Felgner, et al., Proc Natl Acad Sci USA 04:7413-7, 1987; and U.S.
Pat. No. 4,897,355, which are incorporated by reference herein for
their teachings of liposomes. As one example, delivery can be via a
liposome using commercially available liposome preparations such as
LIPOFECTIN, LIPOFECTAMINE (GIBCO-BRL, Inc., Gaithersburg, MID),
SUPERFECT (Qiagen, Hilden, Germany) and TRANSFECTAM (Promega
Biotec, Inc., Madison, Wis.), as well as other liposomes developed
according to procedures standard in the art. Liposomes where the
diffusion of the compound or delivery of the compound from the
liposome is designed for a specific rate or dosage can also be
used.
[0432] As described herein, niosomes are delivery devices that can
be used to deliver the compositions disclosed herein. Noisomes are
multilamellar or unilamellar vesicles involving non-ionic
surfactants. An aqueous solution of solute is enclosed by a bilayer
resulting from the organization of surfactant macromolecules.
Similar to liposomes, noisomes are used in targeted delivery of,
for example, anticancer drugs, including methotrexate, doxorubicin,
and immunoadjuvants. They are generally understood to be different
from transferosomes, vesicles prepared from amphiphilic
carbohydrate and amino group containing polymers, e.g.,
chitosan.
[0433] As described herein, nanoerythrosomes are delivery devices
that can be used to deliver the compositions disclosed herein.
Nanoerythrosomes are nano-vesicles made of red blood cells via
dialysis through filters of defined pore size. These vesicles can
be loaded with a diverse array of biologically active molecules,
including proteins and the compositions disclosed herein. They
generally serve as ideal carriers for antineoplastic agents like
bleomycin, actinomycin D, but can be used for steroids, other
lipids, etc.
[0434] Artificial red blood cells, as described herein, are further
delivery devices that can be used to deliver the compositions
disclosed herein. Artificial red blood cells can be generated by
interfacial polymerization and complex emulsion methods. Generally,
the "cell" wall is made of polyphtaloyl L-lysine
polymer/polystyrene and the core is made of a hemoglobin solution
from sheep hemolysate. Hemoglobin loaded microspheres typically
have particle sizes of from about 1 to about 10 mm. Their size,
flexibility, and oxygen carrying capacity is similar to red blood
cells.
[0435] Solid-lipid nanoparticles, as described herein, are other
delivery devices that can be used to deliver the compositions
disclosed herein. Solid-lipid nanoparticles are nanoparticles,
which are dispersed in an aqueous surfactant solution. They are
comprised of a solid hydrophobic core having a monolayer of a
phospholipid coating and are usually prepared by high-pressure
homogenization techniques. Immunomodulating complexes (ISCOMS) are
examples of solid-lipid nanoparticles. They are cage-like 40 nm
supramolecular assemblies comprising of phospholipid, cholesterol,
and hydrophobic antigens and are used mostly as immunoadjuvants.
For instance, ISCOMs are used to prolong blood-plasma levels of
subcutaneously injected cyclosporine.
[0436] Microspheres and micro-capsules, as described herein, are
yet other delivery devices that can be used to deliver the
compositions disclosed herein. In contrast to liposomal delivery
systems, microspheres and micro-capsules typically do not have an
aqueous core bat a solid polymer matrix or membrane. These delivery
devices are obtained by controlled precipitation of polymers,
chemical cross-linking of soluble polymers, and interfacial
polymerization of two monomers or high-pressure homogenization
techniques. The encapsulated compound is gradually released from
the depot by erosion or diffusion from the particles. Successful
formulations of short acting peptides, such as LHRH agonists like
leuprorelin and triptoreline, have been developed. Poly(lactide
co-glycolide (PLGA) microspheres are currently used as monthly and
three monthly dosage forms in the treatment of advanced prostrate
cancer, endometriosis, and other hormone responsive conditions.
Leuprolide, superagonist, was incorporated into a variety of PLGA
matrices using a solvent extraction/evaporation method. As noted,
all of these delivery devices can be used in the methods disclosed
herein.
[0437] Pulmospheres are still other examples of delivery devices
that can be used herein. Pulmospheres are hollow porous particles
with a low density (less than about 0.1 gm/mL). Pulmospheres
typically have excellent re-dispersibility and are usually prepared
by supercritical fluid condensation technology. Co-spray-drying
with certain matrices, such as carbohydrates, human serum albumin,
etc., can improve the stability of proteins and peptides (e.g.,
insulin) and other biomolecules for pulmonary delivery. This type
of delivery could be also accomplished with micro-emulsions and
lipid emulsions, which are ultra fine, thin, transparent
oil-in-water (o/w) emulsions formed spontaneously with no
significant input of mechanical energy. In this technique, an
emulsion can be prepared at a temperature, which should be higher
than the phase inversion temperature of the system. At elevated
temperature the emulsion is of water-in-oil (w/o) type and as it
cools at the phase inversion temperature, this emulsion is inverted
to become o/w. Due to their very small inner phase, they are
extremely stable and used for sustained release of steroids and
vaccines. Lipid emulsions comprise a neutral lipid core (i.e.,
triglycerides) stabilized by a monolayer of amphiphilic lipid
(i.e., phospholipid) using surfactants like egg lecithin
triglycerides and miglyol. They are suitable for passive and active
targeting.
[0438] There are other oral delivery systems under investigation
that are based on osmotic pressure modulation, pH modulation,
swelling modulation, altered density and floating systems,
mucoadhesiveness etc. These formulations and time-delayed
formulations to deliver drugs in accordance with circadian rhythm
of disease that are currently in use or investigation can be
applied for delivery of the compositions disclosed herein.
[0439] It is also contemplated that the disclosed ionic liquid
compositions can be formulated as part of a controlled release
vehicle. For example, microspheres and microcapsules, implants, and
the like containing liquid bioactive agents are well known, as are
methods for their preparation. As such, these methods can be used
with the disclosed ionic liquid compositions to produce controlled
release vehicles that can release the disclosed ionic liquid
composition with a desired release profile.
[0440] Also contemplated are pills prepared from the disclosed
ionic liquid compositions that are glasses. For example, a glass
ionic liquid composition can be cooled to form a pill. That is,
glasses are "cast-able" above their glass transition temperature
(T.sub.g) into shapes with specific surface areas, allowing
predictable release/Pharmacokinetic properties. Below T.sub.g,
these disclosed glass ionic liquid composition can be milled into
specific shapes and sizes. Alternatively, the disclosed ionic
liquid compositions can be tableted as liquids that upon cooling
form glasses. Such a method can allow the homogeneous distribution
of a pharmaceutical active into the tablet.
[0441] A particular example includes ionic liquid compositions that
are in the glass form but melt at or slightly above body
temperature. Such compositions can allow formulation as a solid,
but have known solubility, bioavailability, etc. as a liquid. These
compositions can have uses in, for example, bandages, patches, or
wound dressings. Further, glass compositions that "melt" slightly
above room temperature can be "melted" by a consumer or physician
with, e.g., hot water or body heat, and "painted" onto an area of
interest (infected area). Cooling of the composition can then
provide a thin, solid coating of material which is both a slow
release form of an active ingredient ion (e.g., anti-infective,
steroid, anesthetic, or combination thereof), plus serve as a
physical barrier.
[0442] Further, the disclosed ionic liquids can be used as carriers
for other active compounds, many of which are disclosed herein. For
example, prodrugs, ionic and neutral active molecules can be
dissolved in the disclosed ionic liquid compositions.
[0443] Further methods of administration can include incorporating
the disclosed ionic liquid composition in to a food stuff or
beverage, which can be ingested by a subject.
[0444] The disclosed ionic liquids can also be encapsulated in a
polymer matrix by methods known in the art.
[0445] Also, the disclosed ionic liquid compositions can be
dissolved in a suitable solvent or carrier as are disclosed herein.
This method can enhance the delivery of one or more active ions in
the ionic liquid. Further, as is disclosed herein, this method can
create a synergistic effect among the various ions present. While
not wishing to be bound by theory, the dissociate coefficient of
various ions in an ionic liquid can be different in different
solvents. Thus, ions in an ionic liquid can dissociate freely in
one solvent and cluster in another. This phenomenon can be utilized
to provide formulations of compound that are difficult to deliver
(e.g., increase the water solubility of steroids). That is,
compounds can be formed into an ionic liquid, as described herein,
and then dissolved in a suitable solvent to provide an easily
deliverable solution. A synertistic effect can be observed upon
administration to a subject, when ions cluster and act together,
rather than independently.
EXAMPLES
[0446] The following examples are set forth below to illustrate the
methods and results according to the disclosed subject matter.
These examples are not intended to be inclusive of all aspects of
the subject matter disclosed herein, but rather to illustrate
representative methods and results. These examples are not intended
to exclude equivalents and variations of the present invention
which are apparent to one skilled in the art.
[0447] Efforts have been made to ensure accuracy with respect to
numbers (e.g., amounts, temperature, etc.) but some errors and
deviations should be accounted for. Unless indicated otherwise,
parts are parts by weight, temperature is in .degree. C. or is at
ambient temperature, and pressure is at or near atmospheric. There
are numerous variations and combinations of reaction conditions,
e.g., component concentrations, temperatures, pressures and other
reaction ranges and conditions that can be used to optimize the
product purity and yield obtained from the described process. Only
reasonable and routine experimentation will be required to optimize
such process conditions. All chemicals used were of analytical
grade, purchased from Sigma-Aldrich (Milwaukee, Wis.), and used
without further purification unless otherwise noted.
Example I
Didecyldimethylammonium Saccharinate [DDA][Sac]
[0448] To the reaction flask, equipped with stirring bar and
thermometer, 0.03 mol of didecyldimethylammonium bromide and 0.03
mol of saccharin sodium salt, and 50 mL of water were put in. The
mixture was intensively stirred for one hour at room temperature.
Afterwards 50 mL of chloroform was added. After phases separated,
chloroform phase was isolated (separated), and washed with fresh
distilled water (so many times) until all chloride ions were washed
oat (removed). Chloroform was distilled off (evaporated) and the
residue (remains) was dried at 60.degree. C. in vacuum.
Saccharinate in form of liquid, with high viscosity was obtained in
95% yield. It is hydrophobic liquid (fluid), lighter than water,
poorly dissolvable in cold and warm water. Thermal stability of
this salt is presented in Table 2. Synthesized salt appear to be
sweet and active against microorganisms. The activity is high in
comparison with starting material, didecyldimethylammonium
chloride, which is confirmed by MIC and MBC values (Table 3 and
Table 4).
[0449] Elemental analysis: CHN: C.sub.29H.sub.52N.sub.2O.sub.3S
(508.80) calculated values: C=68.46%, H=10.30%, N=5.51%;
experimental values C=68.78%, H=10.69%, N=5.31%. .sup.1H NMR
(DMSO-d.sub.6) cation: 3.22 (m, 4H); 3.00 (s, 6H); 1.63 (m, 4H);
1.24 (m, 28H); 0.85 (t, J=7 Hz, 6H); anion: 7.58 (m, 4H); .sup.13C
NMR cation: 62.7; 49.9; 31.2; 28.8; 28.7; 28.6; 28.4; 25.6; 22.0;
21.6; 13.8; anion: 167.7; 145.2; 134.8; 131.3, 130.8; 122.3;
118.9.
TABLE-US-00002 TABLE 2 Thermal stability data of synthesized salts
Temperature [BA][Sac] [DDA][Sac] [BA][Ace] [DDA][Ace] T.sub.g -52.5
-58 T.sub.c 21.5 18.0 26.4 -45.5 T.sub.s-s 65.5 T.sub.m 82.5 22.5
89 -29 T.sub.onset(5%) 176 184 186 182 T.sub.onset 206 211 (203)258
201 T.sub.d 22.7 221 (225)273 245 T.sub.g--glass transition.
T.sub.c--crystallization temperature recorded by the DSC.
T.sub.s-s--solid-solid transitions recorded by the DSC.
T.sub.m--melting point recorded by the DSC. T.sub.onset(5%) --onset
temperature for 5% of the decomposition, T.sub.onset--onset
temperature of the decomposition, T.sub.d--temperature of total
decomposition.
TABLE-US-00003 TABLE 3 MIC* values for investigated salts [BA]
[DDA] [BA] [DDA] culture [Sac] [Sac] [Ace] [Ace] BAC** DDAC*** S.
aureus 4 4 4 8 2 2 E. faecium 8 8 8 8 4 4 E. coli 16 16 31.2 16 8 8
C. albicans 16 16 16 16 8 8 Average 11 11 14.8 12 5.5 5.5 value *in
ppm. **benzalkonium chloride. ***didecyldimethylammonium
chloride
TABLE-US-00004 TABLE 4 MBC* values for investigated salts. [BA]
[DDA] [BA] [DDA] Culture [Sac] [Sac] [Ace] [Ace] BAC** DDAC*** S.
aureus 31.2 62.5 31.2 16 62.5 31.2 E. faecium 16 16 31.2 31.2 31.2
31.2 E. coli 62.5 16 125 62.5 62.5 31.2 C. albicans 31.2 16 31.2 16
16 16 Average 35.2 27.6 54.7 31.4 43.1 27.4 value *in ppm.
**benzalkonium chloride. ***didecyldimethylammonium chloride
Example II
Benzalkonium Saccharinate [BA][Sac]
[0450] To the saturated water solution of saccharin sodium, the
water solution of benzalkonium chloride (alkyl substituent--dodecyl
and tetradecyl) was added in the molar ratio of 1:1.5. The mixture
was stirred for 1 h at the temperature of 60.degree. C. After the
mixture was cooled down to the room temperature, white wax was
formed. The wax was dissolved in chloroform. Chloroform phase was
washed with fresh distilled water (so many times) until all
chloride ions were washed out (removed). The progress was monitored
by using water solution of AgNO.sub.3. Afterwards chloroform was
distilled off (evaporated) and the residue (remains) wax was dried
at 50.degree. C. in vacuum. Synthesized benzalkonium saccharinate
was obtained with 98% yield. It is very sweet in taste. Obtained
wax is poorly dissolvable in cold and warm water. Crystalline
benzalkonium saccharinate, with the melting point of 80-82.degree.
C., was obtained form the mixture of dry (no water) acetone and
diethylether in the volume ratio of 10:1.
[0451] .sup.1H NMR (DMSO-d.sub.6) 7.59 (m, 9H), 4.53 (s, 2H), 3.24
(m, 2H), 2.95 (s, 6H), 1.77 (m, 2H), 1.24 (m, 20H), 0.85 (t, J=7
Hz, 3H); .sup.13C NMR cation: 132.8, 130.1, 128.8, 128.0, 66.1,
63.4, 49.0, 31.2, 28.9, 28.85, 28.7, 28.6, 28.4, 25.7, 22.0, 21.7,
13.8, anion: 167.7, 145.2, 134.8, 131.4, 130.8, 122.3, 118.9.
Example III
Benzalkonium Acesulfamate [BA][Ace]
[0452] To the reactor the water solution of 1 mol of benzalkonium
chloride (alkyl substituent is the mixture of the following groups:
octyl, decyl, dodecyl, tetradecyl, hexadecyl and octydecyl) and
water solution of 1.5 mol of acesulfamate sodium were put in
(placed). The mixture was stirred for 1 h at the temperature of
60.degree. C. After the mixture was cooled down to the room
temperature. Formed wax was dissolved in chloroform and separated
water phase was removed. Chloroform phase was washed with fresh
distilled water (so many times) until all chloride ions were washed
out (removed). The progress was monitored by using water solution
of AgNO.sub.3. Chloroform was distilled off (evaporated) and the
product dried at 60.degree. C. in vacuum. Obtained wax, with the
95% yield, was crystallized out (re-crystallized) from the mixture
of THF, acetone and diethylether in the volume ratio of 10:10:1.
Crystalline benzalkonium acesulfamate, which has sweet taste, melts
between 90 and 91.degree. C. The melting point recorded on the by
the DSC (diffraction scanning calorimeter) was 89.degree. C. This
salt is poorly dissolvable in cold and warm water.
[0453] Measured thermal decomposition temperature of obtained salt
are placed in Table 2, while biological activity data in Table 3
and Table 4. Calculated average values for MIC and MBC indicate
high activity of the salt, slightly lower than that of the starting
benzalkonium chloride
[0454] .sup.1H NMR (DMSO-d.sub.6) cation: 7.52 (m, 5H), 4.53 (s,
2H), 3.24 (m, 2H), 2.95 (s, 6H), 1.78 (m, 2H), 1.25 (m, 20H), 0.85
(t, J=7 Hz, 3H), anion: 5.28 (s, 1H), 1.90 (s, 3H); .sup.13C NMR
cation: 132.8, 130.1, 128.8, 128.0, 66.1, 63.4, 49.0, 31.2, 28.9,
28.87, 28.7, 28.6, 28.4, 25.7, 22.0, 21.7, 13.8, anion: 167.6,
159.5, 102.0, 19.3.
Example IV
Didecyldimethylammonium Acesulfamate [DDA][Ace]
[0455] 0.03 mol of didecyldimethylammonium bromide, in form of gel
(75%) in water, and water solution of 0.03 mol (6.04 g) of
acesulfamate potassium salt were put in (placed) into the reactor.
The mixture was stirred for 1 h at the room temperature. Afterwards
50 mL of chloroform was added. Water phase was separated and
chloroform phase was washed with fresh distilled water (so many
times) until all chloride ions were washed out (removed). The
progress was monitored by using water solution of AgNO.sub.3. After
the chloroform was evaporated, the liquid (fluid) was obtained with
94% yield, and dried at 65.degree. C. in vacuum.
[0456] The hydrophobic, sweet liquid, with high viscosity, lighter
than water and thermally stable was obtained (Table 2). Calculated
MIC and MBC values are shown in the Table 3 and Table 4. Comparing
average values of MIC and MBC for the synthesized salt with the
values for didecyldimethylammonium chloride the only slight
difference in the biological activity is seen (recorded).
[0457] Elemental analysis: CHN: C.sub.26H.sub.52N.sub.2O.sub.4S
(488.77) calculated values C=63.89%, H=10.72%, N=5.73%;
experimental values C=64.09%, H=10.99%, N=5.41%. .sup.1H NMR
(DMSO-d.sub.6) cation: 3.22 (m, 4H), 2.99 (s, 6H), 1.63 (m, 4H),
1.26 (m, 28H), 0.86 (t, J=7 Hz, 6H), anion: 5.26 (q, J=1 Hz, 1H),
1.89 (d, J=2 Hz, 3H); .sup.13C NMR cation: 62.7, 49.8, 31.2, 28.8,
28.7, 28.6, 28.4, 25.7, 22.0, 21.6, 13.8, anion: 167.6, 159.4,
102.0, 19.3.
[0458] In the biological activity measurements (tests) following
bacteria were used: Staphylococcus aureus ATCC 6538, Enterococcus
fuecium ATCC 49474, Escherichia coli ATCC 25922 and fungi Candida
albicans ATCC 10231.
[0459] Microbiological activity tests were performed using
dissolution method. Determinations were performed on liquid base
(background): Mueller-Hinton for bacteria and Sabouraud for fungi.
Starting solution had the concentration of 1 g/cm.sup.3. From this
solution, all other solutions (lower concentrations) were prepared.
To those solutions, 0.1 cm.sup.3 of the suspensions of standard
microorganisms at a concentration of 10.sup.6 cfu cm.sup.3 were
added. The samples with bacteria were incubated for 24 h at the
temperature of 37.degree. C., and with fungi there were incubated
for 48 h at the temperature of 22.degree. C. After incubation time
the MIC, Minimal Inhibitory Concentration, minimal concentration of
the investigated compound at which the growth of the microorganisms
is stopped (visually), was specified (recorded) for every sample.
To define the MBC, Minimal Bactericidal Concentration, additionally
to each solution the 10.sup.-6 cm.sup.3 of the inactivator was
added on the base (background) (0.3% lecithin, 3% polysorbate 80
and 0.1% L-cysteine). The samples with bacteria were incubated for
48 h in the temperature of 37.degree. C. The fungi samples were
incubated for 5 days at the temperature of 22.degree. C. MBC values
were defined (specified) as the concentration at which the level of
the reduction of the microorganisms was not lower than 99.99%.
Example V
Benzalkonium Sulfacetamide
[0460] Benzalkonium chloride (0.001 mol) was dissolved in 60 mL of
distilled water by gentle heating and stirring. Sodium
sulfacetamide (0.001 mol) was dissolved in 60 of distilled water by
gentle heating and stirring. The two solutions were combined and
the reaction mixture was heated and stirred for 30 minutes. The
reaction mixture cooled to room temperature and then 60 mL of
chloroform was added. The reaction mixture was stirred for an
additional 30 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of chloride anions was
monitored by silver nitrate test. A rotary evaporator removed the
chloroform and a yellowish gel was obtained in 76.99% yield.
.sup.1H and .sup.13C NMR (DMSO) were obtained. Melting point (hot
plate apparatus)=35.40.degree. C. Thermal data determined by
thermalgravimetric analysis (TGA): T.sub.onset5%=164.degree. C. and
T.sub.onset=181.degree. C.
Example VI
Didecyldimethylammonium Sulfacetamide
[0461] Didecyldimethylammonium bromide (0.001 mol) was dissolved in
60 of distilled water by gentle heating and stirring. Sodium
sulfacetamide (0.001 mol) was dissolved in 60 mL of distilled water
by gentle heating and stirring. The two solutions were combined and
the reaction mixture was heated and stirred for 30 minutes. The
reaction mixture cooled to room temperature and then 60 mL of
chloroform was added. The reaction mixture was stirred for an
additional 30 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of chloride anions was
monitored by silver nitrate test. A rotary evaporator removed the
chloroform and a yellowish gel was obtained in 87.74% yield,
.sup.1H and .sup.13C NMR (DMSO) were obtained. Melting point (hot
plate apparatus)=25-30.degree. C. Thermal data determined by
thermalgravimetric analysis (TGA): T.sub.onset5%=183.3.degree. C.
and T.sub.onset=200.2.degree. C.
Example VII
Hexadecylpyridinium Sulfacetamide
[0462] Hexadecylpyridinium chloride (0.001 mol) was dissolved in 60
mL of distilled water by gentle heating and stirring. Sodium
sulfacetamide (0.001 mol) was dissolved in 60 mL of distilled water
by gentle heating and stirring. The two solutions were combined and
the reaction mixture was heated and stirred for 30 minutes. The
reaction mixture cooled to room temperature and then 60 mL of
chloroform was added. The reaction mixture was stirred for an
additional 30 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of chloride anions was
monitored by silver nitrate test. A rotary evaporator removed the
chloroform and an orange wax was obtained in 99.22% yield. .sup.1H
and .sup.13C NMR (DMSO) were obtained. Melting point (hot plate
apparatus)=30-40.degree. C. Thermal data determined by
thermalgravimetric analysis (TGA): T.sub.onset5%=211.degree. C. and
T.sub.onset=219.degree. C.
Example VIII
Benzalkonium Ibuprofen
[0463] Benzalkonium chloride (0.001 mol) was dissolved in 60 mL of
distilled water by gentle heating and stirring. Ibuprofen (0.001
mol) was dissolved in 60 mL of distilled water by gentle heating
and stirring. The two solutions were combined and the reaction
mixture was heated and stirred for 30 minutes. The reaction mixture
cooled to room temperature and then 60 mL of chloroform was added.
The reaction mixture was stirred for an additional 30 minutes. The
two phases were separated and the chloroform phase was washed
several times with cool distilled water to remove any inorganic
salt. The presence of chloride anions was monitored by silver
nitrate test. A rotary evaporator removed the chloroform and a %
yield. .sup.1H and .sup.13C NMR (DMSO) were obtained. Melting point
(hot plate apparatus)=.degree. C. Thermogravimetric analysis:
T.sub.g=-41.1.degree. C., T.sub.onset5%=133.degree. C. and
T.sub.onset=153.degree. C.
Example IX
Didecyldimethylammonium Ibuprofen
[0464] Didecyldimethylammonium bromide (0.001 mol) was dissolved in
60 mL of distilled water by gentle heating and stirring. Ibuprofen
(0.001 mmol) was dissolved in 60 mL of distilled water by gentle
heating and stirring. The two solutions were combined and the
reaction mixture was heated and stirred for 30 minutes. The
reaction mixture cooled to room temperature and then 60 mL of
chloroform was added. The reaction mixture was stirred for an
additional 30 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of chloride anions was
monitored by silver nitrate test. A rotary evaporator removed the
chloroform and a % yield. .sup.1H and .sup.13C NMR (DMSO) were
obtained. Melting point (hot plate apparatus)=.degree. C.
Thermogravimetric analysis: T.sub.g=-57.1.degree. C.,
T.sub.onset5%=153.degree. C. and T.sub.onset=172.degree. C.
Example X
Didecyldimethylammonium Trans-Cinnamate
[0465] Didecyldimethylammonium bromide (0.001 mol) was dissolved in
50 mL of hot distilled water, trans-Cinnamic acid (0.001 mol) was
added to the didecyldimethylammonium solution. The reaction
solution was stirred at 90.degree. C. for 4 h. The reaction
solution was cooled to room temperature and then 60 mL of
chloroform was added. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of chloride anions was
monitored by silver nitrate test. A rotary evaporator removed the
chloroform and a wax was obtained in 93% yield. .sup.1H and
.sup.13C NMR (DMSO) were obtained. Melting point (hot plate
apparatus)=54-55.degree. C.
Example XI
Benzalkonium Trans-Cinnamate
[0466] Benzalkonium chloride (0.001 mol) was dissolved in warm
distilled water, trans-Cinnamic acid (0.001 mol) was added to the
benzalkonium solution. The reaction solution was stirred at
90.degree. C. for 4 hours. The reaction solution was cooled to room
temperature then 60 mL of chloroform was added. The two phases were
separated and the chloroform phase was washed several times with
cool distilled water to remove any inorganic salt. The presence of
chloride anions was monitored by silver nitrate test. A rotary
evaporator removed the chloroform and an orange viscous liquid was
obtained in 90% yield. .sup.1H and .sup.13C NMR (DMSO) were
obtained. Melting point (hot plate apparatus)=at room
temperature.
Example XII
Hexadecylpyridinium Colawet MA-80
[0467] Hexadecylpyridinium chloride (0.001 mol) was dissolved in 60
mL of distilled water by gentle heating and stirring. Sodium
dihexylsulfosuccinate (Colawet MA-80 from Colonial Chemicals, South
Pittsburg, Tenn.; 0.001 mol) was dissolved in 60 mL of distilled
water by gentle heating and stirring. The two solutions were
combined and the reaction mixture was heated and stirred for 30
minutes. The reaction mixture cooled to room temperature and then
60 mL of chloroform was added. The reaction mixture was stirred for
an additional 30 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of chloride anions was
monitored by silver nitrate test. A rotary evaporator removed the
chloroform and a yellowish viscous liquid was Obtained in 96.93%
yield. .sup.1H and .sup.13C NMR (DMSO) were obtained. Melting point
(hot plate apparatus)=at room temperature. Thermal data determined
by thermalgravimetric analysis (TGA): T.sub.onset5%=248.degree. C.
and T.sub.onset=262.degree. C.
Example XIII
Didecyldimethylammonium Colawet MA-80
[0468] Decyldimethylammonium bromide (0.001 mol) was dissolved in
60 mL of distilled water by gentle heating and stirring. Sodium
dihexylsulfosuccinate (Colawet MA-80 from Colonial Chemicals, South
Pittsburg, TN; 0.001 mol was dissolved in 60 mL of distilled water
by gentle heating and stirring. The two solutions were combined and
the reaction mixture was heated and stirred for 30 minutes. The
reaction mixture cooled to room temperature and then 60 mL of
chloroform was added. The reaction mixture was stirred for an
additional 30 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of chloride anions was
monitored by silver nitrate test. A rotary evaporator removed the
chloroform and a yellowish viscous liquid was obtained in 96.93%
yield. .sup.1H and .sup.13C NMR (DMSO) were obtained. Melting point
(hot plate apparatus)-=liquid at room temperature. Thermal data
determined by thermalgravimetric analysis (TGA):
T.sub.onset5%=218.degree. C. and T.sub.onset=226.degree. C.
Example XIV
Benzalkonium Colawet MA-80
[0469] Benzalkonium chloride (0.001 mol) was dissolved in 60 mL of
distilled water by gentle heating and stirring. Sodium
dihexylsulfosuccinate (Colawet MA-80 from Colonial Chemicals, South
Pittsburg, Tenn.; 0.001 mol) was dissolved in 60 mL of distilled
water by gentle heating and stirring. The two solutions were
combined and the reaction mixture was heated and stirred for 30
minutes. The reaction mixture cooled to room temperature and then
60 mL of chloroform was added. The reaction mixture was stirred for
an additional 30 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of chloride anions was
monitored by silver nitrate test. A rotary evaporator removed the
chloroform and a clear viscous liquid was obtained in 75.56% yield.
.sup.1H and .sup.13C NMR (DMSO) were obtained. Melting point (hot
plate apparatus)=at room temperature. Thermal data determined by
thermalgravimetric analysis (TGA): T.sub.onset5%=223.degree. C. and
T.sub.onset=262.degree. C.
Example XV
Didecyldimethylammonium Fast Green FCF
[0470] Didecyldimethylammonium bromide (0.003 mot) was dissolved in
100 mL of distilled water by gentle heating and stirring. Fast
Green FCF (0.001 mol) was dissolved in 60 mL of distilled water by
gentle heating and stirring. The two solutions were combined and
the reaction mixture was heated and stirred for 30 minutes. The
reaction mixture cooled to room temperature and then 60 mL of
chloroform was added. The reaction mixture was stirred for an
additional 30 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of chloride anions was
monitored by silver nitrate test. A rotary evaporator removed the
chloroform and a dark blue liquid was obtained in 65.54% yield.
Melting point (hot plate apparatus)=liquid at room temperature.
Thermal data determined by thermalgravimetric analysis (TGA):
T.sub.onset5%=194.degree. C. and T.sub.onset=200.degree. C.
Example XVII
Hexadecylpyridinium Fast Green FCF
[0471] Hexadecylpyridinium chloride (0.003 mol) was dissolved in
100 mL of distilled water by gentle heating and stirring. Fast
Green FCF (0.001 mol) was dissolved in 60 mL of distilled water by
gentle heating and stirring. The two solutions were combined and
the reaction mixture was heated and stirred for 30 minutes. The
reaction mixture cooled to room temperature and then 60 mL of
chloroform was added. The reaction mixture was stirred for an
additional 30 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of chloride anions was
monitored by silver nitrate test. A rotary evaporator removed the
chloroform and a dark blue solid was obtained in 28.14% yield.
Melting point (hot plate apparatus)=40-50.degree. C. Thermal data
determined by thermalgravimetric analysis (TGA):
T.sub.onset5%=216.degree. C. and T.sub.onset=218.degree.
C./307.degree. C./504.degree. C.
Example XVIII
Benzalkonium Fast Green FCF
[0472] Benzalkonium chloride (0.003 mol) was dissolved in 100 mL of
distilled water by gentle heating and stirring. Fast Green FCF
(0.001 mol) was dissolved in 60 mL of distilled water by gentle
heating and stirring. The two solutions were combined and the
reaction mixture was heated and stirred for 30 minutes. The
reaction mixture cooled to room temperature and then 60 mL of
chloroform was added. The reaction mixture was stirred for an
additional 30 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of chloride anions was
monitored by silver nitrate test. A rotary evaporator removed the
chloroform and a dark blue gel was obtained in 91.52% yield.
Melting point (hot plate apparatus)=35-45.degree. C. Thermal data
determined by thermalgravimetric analysis (TGA):
T.sub.onset5%=136.degree. C. and T.sub.onset=195.degree. C.
Example XIX
Hexadecylpyridinium
[0473] Hexadecylpyridinium chloride (0.001 mol) was dissolved in 60
mL of distilled water by gentle heating and stirring. Sodium
piperacillin (0.001 mol) was dissolved in 60 mL of distilled water
by gentle heating and stirring. The two solutions were combined and
the reaction mixture was heated and stirred for 30 minutes. The
reaction mixture cooled to room temperature, and then 60 mL of
chloroform was added. The reaction mixture was stirred for an
additional 30 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of chloride anions was
monitored by silver nitrate test. A rotary evaporator removed the
chloroform and a soft orange solid was obtained in 58.66% yield.
Melting point (hot plate apparatus)=30-40.degree. C.
Example XX
Didecyldimethylammonium Piperacillin
[0474] Didecyldimethylammonium bromide (0.001 mol) was dissolved in
60 mL of distilled water by gentle heating and stirring. Sodium
piperacillin (0.001 mol) was dissolved in 60 mL of distilled water
by gentle heating and stirring. The two solutions were combined and
the reaction mixture was heated and stirred for 30 minutes. The
reaction mixture cooled to room temperature and then 60 mL of
chloroform was added. The reaction mixture was stirred for an
additional 30 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of chloride anions was
monitored by silver nitrate test. A rotary evaporator removed the
chloroform and a clear gel was obtained in 50.65% yield. .sup.1H
and .sup.13C NMR (DMSO) were obtained. Melting point (hot plate
apparatus)=25-30.degree. C. Thermal data determined by
thermalgravimetric analysis (TGA): T.sub.onset5%=181.degree. C. and
T.sub.onset=205.degree. C.
Example XXI
Benzalkonium Piperacillin
[0475] Benzalkonium chloride (0.001 mol) was dissolved in 60 mL of
distilled water by gentle heating and stirring. Sodium piperacillin
(0.001 mol) was dissolved in 60 mL of distilled water by gentle
heating and stirring. The two solutions were combined and the
reaction mixture was heated and stirred for 30 minutes. The
reaction mixture cooled to room temperature and then 60 mL of
chloroform was added. The reaction mixture was stirred for an
additional 30 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of chloride anions was
monitored by silver nitrate test. A rotary evaporator removed the
chloroform and a cloudy solid was obtained in 26.12% yield. .sup.1H
and .sup.13C NMR (DMSO) were obtained. Melting point (hot plate
apparatus)=30-40.degree. C. Thermal data determined by
thermalgravimetric analysis (TGA): T.sub.onset5%=165.degree. C. and
T.sub.onset=177.degree. C.
Example XXII
Benzalkonium Penicillin G
[0476] Benzalkonium chloride (0.001 mol) was dissolved in 60 mL of
distilled water by gentle heating and stirring. Potassium
penicillin 0 (0.001 mol) was dissolved in 60 mL of distilled water
by gentle heating and stirring. The two solutions were combined and
the reaction mixture was heated and stirred for 30 minutes. The
reaction mixture cooled to room temperature and then 60 mL of
chloroform was added. The reaction mixture was stirred for an
additional 30 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of chloride anions was
monitored by silver nitrate test. A rotary evaporator removed the
chloroform and a yellowish soft solid was obtained in 93.60% yield.
.sup.1H and .sup.13C NMR (DMSO) were obtained. Melting point (hot
plate apparatus)=30-40.degree. C.
Example XXIII
Didecyldimethylammonium Penicillin G
[0477] Didecyldimethylammonium bromide (0.001 mol) was dissolved in
60 mL of distilled water by gentle heating and stirring. Potassium
penicillin G (0.001 mol) was dissolved in 60 mL of distilled water
by gentle heating and stirring. The two solutions were combined and
the reaction mixture was heated and stirred for 30 minutes. The
reaction mixture cooled to room temperature and then 60 mL of
chloroform was added. The reaction mixture was stirred for an
additional 30 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of chloride anions was
monitored by silver nitrate test. A rotary evaporator removed the
chloroform and an orange gel was obtained in 76% yield. .sup.1H and
.sup.13C NMR (DMSO) were obtained. Melting point (hot plate
apparatus)=25-30.degree. C.
Example XXIV
Hexadecylpyridinium G
[0478] Hexadecylpyridinium chloride (0.001 mol) was dissolved in 60
mL of distilled water by gentle heating and stirring. Potassium
penicillin G (0.001 mol) was dissolved in 60 mL of distilled water
by gentle heating and stirring. The two solutions were combined and
the reaction mixture was heated and stirred for 30 minutes. The
reaction mixture cooled to room temperature and then 60 mL of
chloroform was added. The reaction mixture was stirred for an
additional 30 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of chloride anions was
monitored by silver nitrate test. A rotary evaporator removed the
chloroform and an orange gel was obtained in about 99% yield.
Melting point (hot plate apparatus)=35-40.degree. C.
Example XXV
Didecyldimethylammonium Salicylate
[0479] Didecyldimethylammonium bromide (0.03 mol) (tech., 75% gel
in water) was dissolved in 50 mL hot, distilled water. Salicylic
acid (0.03 mol) was added to the solution. The mixture was stirred
vigorously at 90.degree. C. for 4 h. After cooling to room
temperature, 60 mL of chloroform was added. Chloroform phase was
washed with distilled water until bromide ions were no longer
detected using AgNO.sub.3. The obtained wax (93% yield) was dried
in vacuum. Thermogravimetric analysis: T.sub.c=-1.0.degree. C.,
T.sub.m=30.4.degree. C., T.sub.onset5%=169.degree. C. and
T.sub.onset=200.degree. C. .sup.1H and .sup.13C NMR (DMSO) were
obtained.
Example XXVI
Benzalkonium Salicylate
[0480] Benzalkonium chloride (0.03 mol) was dissolved in warm
distilled water and stechiometric amount of salicylic acid was
added. The reaction mixture was stirred at 90.degree. C. for 4 h.
After cooling, chloroform was added. The organic phase was washed
with distilled water until chloride ions were no longer detected
using AgNO.sub.3. Organic solvent was removed and the residue was
dried in vacuum. Benzalkonium salicylate was obtained with 90%
yield as wax at room temperature; it is soluble in hot water.
Thermogravimetric analysis: T.sub.g=-43.5.degree. C.,
T.sub.onset5%=150.degree. C., and T.sub.onset=180.degree. C.,
.sup.1H and .sup.13C NMR (DMSO) were obtained.
Example XXVII
(2-hydroxyethyl)dimethylundecyloxymethylammonium Benzoate
[0481] 2-(dimethylamino)ethanol (0.05 mol) was dissolved in
anhydrous hexane (20 mL) and a solution of chloromethyl undecyl
ether (0.05 mol) was added dropwise at room temperature. The
reaction mixture was stirred for 15 minutes. The obtained
precipitate was washed with dry hexane (40 mL). The material was
used in the next step, without further purification. The prepared
ammonium chloride was dissolved in water and an aqueous solution of
sodium benzoate (0.07 mol) was added. The solution was stifling for
15 min. After 10 h, the reaction mixture was concentrated using a
rotary evaporator. To a dry crude product, anhydrous acetone (30
mL) was added. The solid product was filtered and acetone was
removed. The product was dried for 10 h at 50.degree. C. vacuum to
obtain (2-hydroxyethyl)dimethylundecyloxymethylammonium benzoate as
a grease in 80% yield. Thermogravimetric analysis:
T.sub.onset=127.degree. C., .sup.1H and .sup.13C NMR (DMSO) were
obtained.
Example XXVIII
(2-acetoxyethyl)heptyloxymethyldimethylammonium Benzoate
[0482] In a two-necked, round bottomed flask, equipped with a
condenser and addition funnel, 2-(dimethylamino)ethyl acetate (0.1
mol) was mixed with 150 mL of anhydrous hexane. Chloromethyl hexyl
ether (0.1 mol) was slowly added over 15 minutes. After 30 minutes,
the reaction mixture was cooled to the temperature of minus
18.degree. C. and the crude product was separated. The crude
product was washed with 100 mL of hexane and used in the next step
without further purification. The material was dissolved in 100 mL
of water and aqueous solution of sodium benzoate was added in
stoichiometric amount. After 30 minutes, two phases were separated.
The water phase was removed and 100 mL of anhydrous acetone was
added to the residue. Precipitated NaCl was filtered off and the
obtained liquid product,
(2-acetoxyethyl)heptyloxymethyldimethylammonium benzoate, was dried
for 12 h at 60.degree. C. in vacuum. The product was obtained as
viscous liquid in 65% yield. Thermogravimetric analysis:
T.sub.onset=120.degree. C. .sup.1H and .sup.13C NMR (DMSO) were
obtained.
Example XXIX
(2-acetoxyethyl)dodecyloxymethyldimethylammonium Benzoate
[0483] In a two-necked, round bottomed flask, equipped with a
condenser and addition funnel, the 2-(dimethylamino)ethyl acetate
(0.05 mol) was mixed with 30 mL of anhydrous hexane. Chloromethyl
dodecyl ether (0.055 mol) was slowly added over 5 minutes. After 15
minutes, the reaction mixture was cooled to the temperature of
minus 18.degree. C. and the crude product was separated. The
precipitate was washed with 30 mL of hexane and used in the next
step without further purification. The crude
(2-acetooxyethyl)-dodecyloxymethyldimethylammonium chloride was
dissolved in 30 mL of water and aqueous solution of potassium
benzoate (0.065 mol) was added. After 30 min., 30 mL of chloroform
was added. The chloroform phase was separated and washed with
distilled water until chloride ions were no longer detected using
AgNO.sub.3. The obtained grease was dried under vacuum. The product
was obtained as grease in 67% yield. Thermogravimetric analysis:
T.sub.onset=122.degree. C. .sup.1H and .sup.13C NMR (DMSO) were
obtained.
Example XXX
Didecyldimethylammonium Salicylate
[0484] Didecyldimethylammonium chloride (0.03 mol) was dissolved in
50 distilled water and sodium salicylate (0.04 mol was added to
solution. The mixture was stirred at 40.degree. C. for 1 h. After
cooling to room temperature, 60 mL of chloroform was added. The
chloroform phase was separated and washed with distilled water
until chloride ions were no longer detected using AgNO.sub.3. The
didecyldimethylammonium salicylate was obtained in 95% yield. The
product is insoluble in water and was dried under vacuum.
Example XXXI
Didecyldimethylammonium Salicylate (Alternative Synthesis)
[0485] The stechiometric amounts of didecyldimethylammonium
saccharinate and sodium salicylate were mixed in distilled water
and stirred at 60.degree. C. for 2 h. After that time the solution
was cooled to room temperature. The product was extracted from the
aqueous solution with chloroform. The chloroform phase was removed
and solvent was evaporated. Synthesized didecyldimethylammonium
salicylate (90% yield) was dried under vacuum.
Example XXXII
Benzalkonium Salicylate
[0486] Benzalkonium saccharinate (0.01 mol) and benzoic acid (0.01
mol) were dissolved in 25 mL of hot acetone. The mixture was
stirred at room temperature for 5 h. Distilled water was added. The
organic phase was separated and washed with distilled water.
Organic phase was evaporated and the product, benzalkonium
salicylate, was dried under vacuum. .sup.1H and .sup.13C NMR (DMSO)
were obtained.
Example XXXIII
Didecyldimethylammonium
2-[(2,6-dichlorophenyl)amino]-benzeneacetate
[0487] Didecyldimethylammonium chloride (0.03 mol) was dissolved in
40 mL distilled water and diclofenac sodium salt (0.04 mol) was
added to the solution. The solution was stirred at room temperature
for 30 min. Chloroform (40 mL) was added to the reaction mixture
and the mixture was stirred. After separation of the phases, the
organic phase was washed with 40 mL distilled, cold water until
chloride ions were no longer detected using AgNO.sub.3. Chloroform
was removed and the residue was dried at 50.degree. C. in vacuum.
The product, didecyldimethylammonium
2-[(2,6-dichlorophenyl)amino]benzeneacetate (100% yield), was
obtained as a grease that is soluble in chloroform, acetone, and
DMSO. The product lacks miscibility with water and hexane.
Thermogravimetric analysis: T.sub.onset5%=162.degree. C., and
T.sub.onset=183.degree. C. .sup.1H and .sup.13C NMR (DMSO) were
obtained.
Example XXXIV
Didecyldimethylammonium
2-[(2,6-dichlorophenyl)amino]-benzeneacetate (Alternative
Synthesis)
[0488] A solution of didecyldimethylammonium acesulfamate (0.01
mol) in acetone was prepared. The aqueous solution of sodium
diclofenac (0.02 mol) was added and the reaction mixture was
stirred at 60.degree. C. for 2 h. The solution was extracted with
ethyl acetate. Organic phase was separated and evaporated. The
product, didecyldimethylammonium
2-[(2,6-dichlorophenyl)amino]benzeneacetate (88% yield), was dried
under vacuum. .sup.1H and .sup.13C NMR, (DMSO) were obtained.
Example XXXV
Didecyldimethylammonium
N-[4-[[(2-amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-L-gl-
utamate
[0489] Didecyldimethylammonium chloride (0.025 mol) was dissolved
in 40 mL distilled water and the folic acid sodium salt (0.01 mol)
was added. The solution was stirred at room temperature for 30 mM.
After separation of the phases, the organic phase was washed with
distilled, cold water until chloride ions were no longer detected
using AgNO.sub.3. The organic phase was separated and solvent was
evaporated. The product (90% yield), didecyldimethylammonium
N-[4-[[(2-amino-1,4-dihydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl]-L-gl-
utamate, was dried at 50.degree. C. under vacuum. Product is
soluble in chloroform, acetone, DMSO, it lacks miscibility with
water and hexane. .sup.1H and .sup.13C NMR (DMSO) were obtained.
Thermogravimetric analysis: T.sub.onset5%=153.degree. C., and
T.sub.onset=201.degree. C. .sup.1H and .sup.13C NMR (DMSO) were
obtained.
Example XXXVI
Didecyldimethylammonium
(S)-6-methoxy-.-methyl-2-naphthaleneacetate
[0490] The stoichiometric mixture (0.025 mol) of
didecyldimethylammonium chloride and naproxen sodium salt were
dissolved in distilled water and stirred at room temperature for 1
h. The product was extracted by ethyl acetate and organic phase was
separated and then washed with distilled water. Ethyl acetate phase
was removed and solvent evaporated. The product,
didecyldimethylammonium (S)-6-methoxy-.-methyl-2-naphthaleneacetate
(95% yield), was dried under vacuum. The product is soluble in
chloroform, acetone, and DMSO. It lacks miscibility with water and
hexane. Thermogravimetric analysis: T.sub.onset5%=156.degree. C.,
and T.sub.onset=190.degree. C., .sup.1H and .sup.13C NMR (DMSO)
were obtained.
Example XXXII
Lidocaine Docusate
[0491] Lidocaine hydrochloride (0.0188 mol) was dissolved in 50
methanol and sodium docusate [bis(2-ethylhexyl)sulfosuccinate
sodium salt] (0.0188 mol) was dissolved in 50 mL. The two solutions
were combined and stirred for two hours, during this time a white
precipitate (NaCl) formed. The methanol was removed by rotary
evaporation which leaves a white sticky solid. To this solid, 150
mL of chloroform was added. A portion of the product dissolved the
chloroform while the byproduct (NaCl) remained as a suspended
solid. The NaCl was removed by filitration, and the solvent was
removed by rotary evaporation. The product, lidocaine docusate, is
a colorless syrup and is dried under high vacuum. .sup.1H and
.sup.13C NMR (CDCl.sub.3) were obtained.
Example XXXVIII
Didecyldimethylammonium Benzoate
[0492] Didecyldimethylammonium chloride (0.02 mol) was dissolved in
distilled water and 0.015 mmol of benzoic acid sodium salt was
added. The solution was stirred at 80.degree. C. for 7 h. The
reaction mixture was extracted by chloroform. Chloroform phase was
removed and washed with distilled, cold water until chloride ions
were no longer detected using AgNO.sub.3. Then chloroform was
removed. Obtained benzoate in 85% yield was dried in vacuum,
.sup.1H NMR and .sup.13C NMR (CDCl.sub.1) were obtained.
Example XXXIX
Benzalkonium Benzoate
[0493] 10 g of benzalkonium chloride (in which alkyl represents a
mixture of the alkyls from C.sub.8H.sub.17 to C.sub.18H.sub.37) was
soluble in distilled water and 7.2 g of sodium benzoate was added.
The reaction mixture was stirred at 90.degree. C. for 6 h. After
cooling, 50 mL of chloroform was added. The organic phase was
washed with distilled water until chloride ions were detected using
AgNO.sub.3. Chloroform was removed and the residue was dried in
vacuum. Benzoate was obtained with 84% yield.
Example XL
(2-hydroxyethyl)cyclododecyloxymethyldimethylammonium Benzoate
[0494] 0.1 mol of
(2-hydroxyethyl)cyclododecyloxymethyldimethylammonium chloride was
dissolved in 100 mL of anhydrous acetone and sodium benzoate was
added. After 5 h of stirring, NaCl was filtered and the reaction
mixture was concentrated using a rotary evaporator. The obtained
was dried for 10 h at 50.degree. C. in vacuum.
Example XLI
Didecyldimethylammonium Mandelate
[0495] To 0.03 mol of didecyldimethylammonium chloride dissolved in
50 mL distilled water was added 0.03 mol of mandelic acid and 0.03
mol of NaOH. The mixture was stirred at 50.degree. C. for 2 h.
After cooling to room temperature, 60 mL of chloroform was added.
Chloroform phase was washed with distilled water until chloride
ions were no longer detected using AgNO.sub.3. The obtained
mandelate with 96% yield is insoluble in water and was dried in
vacuum.
Example XLII
Didecyldimethylammonium 2-acetoxybenzoate
[0496] A stoichiometric mixture of didecyldimethylammonium
chloride, acetylsalicyclic acid, and NaOH in distilled water was
stirred at 60.degree. C. for 2 hand then cooled to room
temperature. The aqueous solution was extracted by chloroform.
Chloroform was removed and prepared didecyldimethylammonium
2-acetoxybenzoate with 90% yield was dried in vacuum.
Example XLIII
Didecyldimethylammonium p-toluenesulfonate
[0497] 0.015 mol of didecyldimethylammonium chloride, 0.01 mol of
p-toluenesulfonic acid, 0.01 mol of NaOH and 100 mL of distilled
water were charged to a round bottomed flask and heated. The
mixture was stirred for 2 h 40.degree. C., whence the phases were
allowed to separate. The organic layer was then washed three times
with distilled water. The aqueous phases were tested for the
presence of chloride ion using silver nitrate solution. Finally,
the organic layer was vacuum stripped to remove water. The obtained
didecyldimethylammonium p-toluenesulfonate with 95% yield is
soluble in chloroform, acetone, DMSO, and insoluble in water and
hexane.
Example XLIV
Didecyldimethylammonium Nicotinate
[0498] To 0.002 mol of didecyldimethylammonium bromide (tech., 75%
gel in water) dissolved in 60 mL hot, distilled water was added
0.002 mol of nicotinic acid. The mixture was stirred vigorously at
90.degree. C. for 4 h. After cooling to room temperature 60 mL of
chloroform was added. Chloroform phase was washed with distilled
water until bromide ions were no longer detected using AgNO.sub.3.
The obtained waxy, white solid was dried in vacuum.
Example XLV
MultiComponent Ionic Liquids
[0499] Multicomponent ionic liquids containing 3 or more different
ions were prepared to show the tenability of the disclosed
compositions and methods. Three ionic liquids were prepared
[0500] 1. benzalkonium, acesulfamate, and saccharinate
[0501] 2. benzalkonium, mepenzolate, and docusate
[0502] 3. hexadecylpyridinium, acesulfamate, and saccharinate
[0503] The ionic liquids were prepared by dissolving each compound
in a common solvent such as water, methanol, or ethanol. The
solutions were combined and stirred. The solvent was then
evaporated to reveal the ionic liquid and the inorganic salt. The
ionic liquid was purified by dissolving it in a solvent, such as
hexane, methanol, or ethanol. The inorganic salt was filtered off.
The solvent was evaporated to produce the pure ionic liquid.
TABLE-US-00005 Ionic Ratio of Liquid ions Form Melting Point
(.degree. C.) % Yield 1 2:1:1 Brownish solid 40-45 75.4% 1 3:1:2
White solid 30-40 82.7% 1 3:2:1 Orange solid 35-45 72.2% 3 2:1:1
Yellow solid 30-35 95.8% 3 3:1:2 Yellow solid 30-40 76.8% 3 3:2:1
Orange solid 30-35 87.3% 2 2:1:3 Colorless gel 2 1:2:3 Clear wax 2
1:1:2 Whitish gel
Example XLVI
Lidocaine Complex of Ag+
[0504] In a reaction vessel charged with a magnetic stirbar and
shielded from light, 1.0 g (5.9 mmol) AgNO.sub.3 was dissolved in
approximately 25 mL of deionized water. In a separate reaction
vessel, similarly shared with a stirbar and shielded from light,
5.51 g (0.024 mol) of lidocaine (free-base form) was
dissolved/suspended in 25 mL of deionized water. To the latter
solution was added in one portion the aqueous solution of silver
nitrate. A copious white precipitate forms quickly, which (all the
while protected from light) was quickly isolated by suction
filtration. The recovered solid was dried in vacuum, and
subsequently recrystallized by slow evaporation of a
methanol/acetonitrile solution to give well-funned colorless
crystals that are moderately light-stable.
Example XLVII
Ranitidine Docusate
[0505] In a reaction vessel charged with a magnetic stirbar, 2.50 g
(7.12 mmol) of Ranitidine hydrochloride was dissolved in
approximately 25 mL of deionized water. In a separate reaction
vessel, similarly charged with a stirbar, 3.17 g (7.12 mmol) of
sodium docusate was dissolved/suspended in 25 mL of warm, deionized
water. To the latter solution was added in one portion the aqueous
solution of sodium docusate. The deep orange-brown milieu was
stirred overnight, after which time the aqueous system was
repeatedly extracted with 100 mL portions of chloroform.
Emulsification of the two phases was quite pronounced, so each time
the system was heated to about 60.degree. C., then allowed to cool
and settle for 5-7 days, after which point the dark chloroform
phase was separated, dried over anhydrous MgSO.sub.4, filtered, and
rotary evaporated to yield a viscous, deep brown-orange oil
(Ranitidine docusate). The two ions have known histamine
H2-receptor antagonist and an emollient properties,
respectively.
Example XLVIII
Silver Docusate
##STR00296##
[0507] In a reaction vessel charged with a magnetic stirbar and
protected from light, 5.0 g (29 mmol) of silver nitrate was
dissolved in approximately 100 mL of deionized water. To the
stirred solution was added, is small portions, 13.1 g (29 mmol) of
sodium docusate. As the docusate was added, the solution became
gradually gelatinous with attendant difficulties in stirring that
were remedied by gently heating the solution. After addition of the
final portion of sodium docusate, the warmed solution/suspension
was stirred overnight, after which point it was rotary evaporated
to yield a slightly tan mass. The mass was extracted with a
chloroform-acetonitrile mixture, into which much of the material
dissolved but some white solid (presumed to be NaNO.sub.3) did not.
The mixture was filtered and evaporated under reduced pressure to
give a soft mass of slightly off-white final product (which should
be stored away from light because it is photosensitive). This
material was soluble in lidocaine docusate, some organic solvents,
and was relatively slow to dissolve in water, doing so to only a
limited degree. The two ions have known antimicrobial and emollient
properties, respectively.
Example XLIX
Benzalkonium Sulfathiazole
##STR00297##
[0509] Benzalkonium chloride (0.003 mol) was dissolved in 100 mL of
distilled water by gentle stirring and heating. Sulfathiazole
sodium (0.003 mol) was dissolved in 60 mL of distilled water by
gentle stirring and heating. The two solutions were combined and
the reaction mixture was stirred and heated for 1 h. The reaction
mixture was cooled to room temperature and 60 mL of chloroform was
added to the reaction mixture. The two phases were separated and
the chloroform phase was washed several times with cool distilled
water to remove any inorganic salt. The presence of chloride ions
was monitored by silver nitrate test. A rotary evaporator removed
the chloroform and an orange wax was obtained in a 50.04% yield.
.sup.1H and .sup.13C NMR (DMSO) were obtained. Melting point (hot
plate apparatus)=40-50.degree. C. Thermal data was determined by
thermalgravimetric analysis: T.sub.onset5%=156.degree. C. and
T.sub.onset=173.degree. C. The benzalkonium ion is a known
antibacterial and the other ion is used to treat, for example,
gonorrhea and other bacterial infections.
Example L
Benzalkonium Docusate
##STR00298##
[0511] Benzalkonium chloride (0.003 mol) was dissolved in 100 mL of
95% ethanol by gentle stirring and heating. Docusate sodium (0.003
mol) was dissolved in 100 mL of 95% ethanol by gentle stirring and
heating. The two solutions were combined and the reaction mixture
was stirred at room temperature for 1 h. A rotary evaporator was
used to remove the 95% ethanol and produced the ionic liquid and
NaCl salt. Hexane was used to dissolve the ionic liquid while the
NaCl salt precipitated. The NaCl salt was filtered from the
reaction solution. A rotary evaporator was used to remove the
hexane and a white solid was obtained in a 78.32% yield. .sup.1H
(DMSO) was obtained. Melting point (hot plate
apparatus)=25-30.degree. C. The two ions have known antibacterial
and emollient properties, respectively.
Example LI
Benzalkonium Thimerosal
##STR00299##
[0513] Benzalkonium chloride (0.003 mol) was dissolved in 100 mL of
95% ethanol by gentle stirring and heating. Thimerosal sodium
(0.003 mol) was dissolved in 100 mL of 95% ethanol by gentle
stirring and heating. The two solutions were combined and the
reaction mixture was stirred at room temperature for 1 h. A rotary
evaporator was used to remove the 95% ethanol and produced the
ionic liquid and NaCl salt. Chloroform was used to dissolve the
ionic liquid while the NaCl salt precipitated. The NaCl salt was
filtered from the reaction solution. A rotary evaporator was used
to remove the chloroform and a clear gel was obtained in a 72.92%
yield. Melting point (hot plate apparatus)=liquid at room
temperature. The benzalkonium ion has known antibacterial
properties and the thimerosal ion is a known preservative in
vaccines, ophthalmic and nasal products, and tattoo inks.
Example LII
Hexadecylpyridinium Valproic Acid
##STR00300##
[0515] Hexadecylpyridinium chloride (0.003 mol) was dissolved in
100 mL of distilled water by gentle stirring and heating. Valproic
acid sodium salt (0.003 mol) was dissolved in 60 mL of distilled
water by gentle stirring and heating. The two solutions were
combined and the reaction mixture was stirred at room temperature
for 1 h. A rotary evaporator was used to remove the 95% ethanol and
produced the ionic liquid and NaCl salt. Tetrahydrofuran (THF) was
used to dissolve the ionic liquid while the NaCl salt precipitated.
The NaCl salt was filtered from the reaction solution. A rotary
evaporator was used to remove the THF and a dark yellow liquid was
obtained in a 77.14% yield. Melting point (hot plate
apparatus)=liquid at room temperature. The two ions are used as an
antibacterial and an anti-convulsant and mood stabilizer in bipolar
disorder, respectively.
Example LIII
Hexadecylpyridinium Sulfathiazole
##STR00301##
[0517] Hexadecylpyridinium chloride (0.003 mol) was dissolved in
100 mL of distilled water by gentle stirring and heating.
Sulfathiazole sodium (0.003 mol) was dissolved in 60 mL of
distilled water by gentle stirring and heating. The two solutions
were combined and the reaction mixture was stirred at room
temperature for 1 h. A rotary evaporator was used to remove the
distilled water and produced the ionic liquid and NaCl salt.
Benzene was used to dissolve the ionic liquid while the NaCl salt
precipitated. The NaCl salt was filtered from the reaction
solution. A rotary evaporator was used to remove the benzene and a
yellow solid was obtained in a 77.22% yield. .sup.1H NMR (DMSO) was
obtained. Melting point (hot plate apparatus)=40-50.degree. C. The
hexadecylpyridinium ion is known to have antibacterial properties
and the sulfathiazole is known for the treatment of gonorrhea and
other bacterial infections.
Example LIV
Mepenzolate Docusate
##STR00302##
[0519] Mepenzolate bromide (0.003 mol) was dissolved in 100 mL 99%
methanol by gentle stirring and heating. Docusate sodium (0.003
mol) was dissolved in 60 mL 99% methanol by gentle stirring and
heating. The two solutions were combined and the reaction mixture
was stirred at room temperature for 1 h. A rotary evaporator was
used to remove the 99% methanol and produced the ionic liquid and
NaBr salt. Hexane was used to dissolve the ionic liquid while the
NaBr salt precipitated. The NaBr salt was filtered from the
reaction solution. A rotary evaporator was used to remove the
hexane and a white wax was obtained in a 62.75% yield. Melting
point (hot plate apparatus)=50-55.degree. C. The two ions are know
to have anticholinergic and emollient properties, respectively.
Example LV
Benzalkonium Mepenzolate Docusate Ratio (1:1:2)
##STR00303##
[0521] Benzalkonium chloride (0.0015 mol) was dissolved in 100 mL
95% ethanol by gentle stirring and heating. Mepenzolate bromide
(0.003 mol) was dissolved in 100 mL 99% methanol by gentle stirring
and heating. Docusate sodium (0.003 mol) was dissolved in 60 mL 95%
ethanol by gentle stirring and heating. The three solutions were
combined and the reaction mixture was stirred at room temperature
for 2 h. A rotary evaporator was used to remove the 95% ethanol and
the 99% methanol. It produced the ionic liquid and NaBr and NaCl
salt. Hexane was used to dissolve the ionic liquid while the NaBr
and NaCl salt precipitated. The NaBr and NaCl salt was filtered
from the reaction solution. A rotary evaporator was used to remove
the hexane and a clear viscous liquid was obtained in a 44.09%
yield. Melting point (hot plate apparatus) liquid at room
temperature. The three ions have known antibacterial,
anticholinergic, and emollient properties.
Example LVI
Benzalkonium Mepenzolate Docusate Ratio (2:1:3)
[0522] Benzalkonium chloride (0.002 mol) was dissolved in 100 mL
95% ethanol by gentle stirring and heating. Mepenzolate bromide
(0.001 mol) was dissolved in 100 mL 99% methanol by gentle stirring
and heating. Docusate sodium (0.003 mol) was dissolved in 60 mL 95%
ethanol by gentle stirring and heating. The three solutions were
combined and the reaction mixture was stirred at room temperature
for 2 h. A rotary evaporator was used to remove the 95% ethanol and
the 99% methanol. It produced the ionic liquid and NaBr and NaCl
salt. Hexane was used to dissolve the ionic liquid while the NaBr
and NaCl salt precipitated. The NaBr and NaCl salt was filtered
from the reaction solution. A rotary evaporator was used to remove
the hexane and a whitish gel was obtained in a 68.84% yield.
Melting point (hot plate apparatus)=liquid at room temperature.
Example LVII
Benzalkonium Mepenzolate Docusate Ratio (1:2:3)
[0523] Benzalkonium chloride (0.001 mol) was dissolved in 100 mL
95% ethanol by gentle stirring and heating. Mepenzolate bromide
(0.002 mol) was dissolved in 100 mL 99% methanol by gentle stirring
and heating. Docusate sodium (0.003 mol) was dissolved in 60 mL 95%
ethanol by gentle stirring and heating. The three solutions were
combined and the reaction mixture was stirred at room temperature
for 2 h. A rotary evaporator was used to remove the 95% ethanol and
the 99% methanol. It produced the ionic liquid and NaBr and NaCl
salt. Hexane was used to dissolve the ionic liquid while the NaBr
and NaCl salt precipitated. The NaBr and NaCl salt was filtered
from the reaction solution. A rotary evaporator was used to remove
the hexane and a clear gel was obtained in a 53.68% yield. Melting
point (hot plate apparatus)=liquid at room temperature.
Example LVIII
Benzalkonium Sulfathiazole Saccharinate Ratio (2:1:1)
##STR00304##
[0525] Benzalkonium chloride (0.003 mol) was dissolved in 100 mL of
distilled water by gentle stirring and heating. Sulfathiazole
sodium (0.0015 mol) was dissolved in 50 mL of distilled water by
gentle stirring and heating. Acesulfamate potassium (0.0015 mmol)
was dissolved in 50 mL of distilled water by gentle stirring and
heating. The three solutions were combined and the reaction mixture
was stirred and heated for 1 h. A rotary evaporator was used to
remove the distilled water. It produced the ionic liquid and NaCl
salt. 99% methanol was used to dissolve the ionic liquid while the
NaCl salt precipitated. The NaCl salt was filtered from the
reaction solution. A rotary evaporator was used to remove the 99%
methanol and an orange gel was obtained in a 97.02% yield. Melting
point (hot plate apparatus)=liquid at room temperature. The first
two ions have known antibacterial properties and the third ion is a
known artificial sweetener.
Example LIX
Benzalkonium Saccharinate Acesulfamate Ratio (2:1:1)
##STR00305##
[0527] Benzalkonium chloride (0.003 mol) was dissolved in 100 mL of
distilled water by gentle stirring and heating. Saccharinate sodium
(0.0015 mol) was dissolved in 50 mL of distilled water by gentle
stirring and heating. Acesulfamate potassium (0.0015 mol) was
dissolved in 50 mL of distilled water by gentle stirring and
heating. The three solutions were combined and the reaction mixture
was stirred and heated for 1 h. A rotary evaporator was used to
remove the distilled water. It produced the ionic liquid and NaCl
and KCl salt. 95% ethanol was used to dissolve the ionic liquid
while the NaCl and KCl salt precipitated. The NaCl and KCl salt was
filtered from the reaction solution. A rotary evaporator was used
to remove the 95% ethanol and a brown solid was obtained in a
75.41% yield. Melting point (hot plate apparatus)=40-45.degree. C.
The first ion has known antibacterial properties and the next two
ions are known artificial sweeteners.
Example LX
Benzalkonium Saccharinate Acesulfamate Ratio (3:1:2)
[0528] Benzalkonium chloride (0.003 mol) was dissolved in 100 mL of
distilled water by gentle stirring and heating. Saccharinate sodium
(0.001 mol) was dissolved in 50 mL of distilled water by gentle
stirring and heating. Acesulfamate potassium (0.002 mol) was
dissolved in 50 mL of distilled water by gentle stirring and
heating. The three solutions were combined and the reaction mixture
was stirred and heated for 1 h. A rotary evaporator was used to
remove the distilled water. It produced the ionic liquid and KCl
and NaCl salt, 95% ethanol was used to dissolve the ionic liquid
while the KCl and NaCl salt precipitated. The KCl and NaCl salt was
filtered from the reaction solution. A rotary evaporator was used
to remove the 95% ethanol and a White solid was obtained in an
82.70% yield. Melting point (hot plate apparatus)=30-40.degree.
C.
Example LXI
Benzalkonium Saccharinate Acesulfamate Ratio (3:2:1)
[0529] Benzalkonium chloride (0.003 mmol) was dissolved in 100 mL
of distilled water by gentle stirring and heating. Saccharinate
sodium (0.002 mol) was dissolved in stmt of distilled water by
gentle stirring and heating. Acesulfamate potassium (0.001 mol) was
dissolved in 50 mL of distilled water by gentle stirring and
heating. The three solutions were combined and the reaction mixture
was stirred and heated for 1 h. A rotary evaporator was used to
remove the distilled water. It produced the ionic liquid and KCl
and NaCl salt. 95% ethanol was used to dissolve the ionic liquid
while the KCl and NaCl salt precipitated. The KCl and NaCl salt was
filtered from the reaction solution. A rotary evaporator was used
to remove the 95% ethanol and a white solid was obtained in a
72.16% yield. Melting point (hot plate apparatus)=35-45.degree.
C.
Example LXII
Hexadecylpyridinium Saccharinate Acesulfamate Ratio (2:1:1)
##STR00306##
[0531] Hexadecylpyridinium chloride (0.003 mol) was dissolved in
100 mL of distilled water by gentle stirring and heating.
Saccharinate sodium (0.0015 mol) was dissolved in 50 mL of
distilled water by gentle stirring and heating. Acesulfamate
potassium (0.0015 mol) was dissolved in 50 mL of distilled water by
gentle stirring and heating. The three solutions were combined and
the reaction mixture was stirred and heated for 1 h. A rotary
evaporator was used to remove the distilled water. It produced the
ionic liquid and KCl and NaCl salt, 99% methanol was used to
dissolve the ionic liquid while the KCl and NaCl salt precipitated.
The KCl and NaCl salt was filtered from the reaction solution. A
rotary evaporator was used to remove the 99% methanol and a yellow
solid was obtained in a 95.78% yield. Melting point (hot plate
apparatus)=30-35.degree. C. The first ion has known antibacterial
properties and the next two ions are known artificial
sweeteners.
Example LXIII
Hexadecylpyridinium Saccharinate Acesulfamate Ratio (3:1:2)
[0532] Hexadecylpyridinium chloride (0.003 mol) was dissolved in
100 mL of distilled water by gentle stirring and heating.
Saccharinate sodium (0.001 mol) was dissolved in 50 mL of distilled
water by gentle stirring and heating. Acesulfamate potassium (0.002
mol) was dissolved in 50 mL of distilled water by gentle stirring
and heating. The three solutions were combined and the reaction
mixture was stirred and heated for 1 h. A rotary evaporator was
used to remove the distilled water. It produced the ionic liquid
and KCl and NaCl salt. 99% methanol was used to dissolve the ionic
liquid while the KCl and NaCl salt precipitated. The KCl and NaCl
salt was filtered from the reaction solution. A rotary evaporator
was used to remove the 99% methanol and a yellowish solid was
obtained in a 76.76% yield. Melting point (hot plate
apparatus)=30-40.degree. C.
Example LXIV
Diundecyldimethlammonium Saccharinate
##STR00307##
[0534] Diundecyldimethlammonium bromide (0.0023 mol) was dissolved
in 7 mL of distilled water by gentle heating and stirring. Sodium
saccharinate (0.001 mol) was dissolved in 7 mL of distilled water
by gentle heating and stirring. The two solutions were combined and
the reaction mixture was heated and stirred for 90 minutes. The
reaction mixture was cooled to room temperature and then 7 mL of
chloroform was added. The reaction mixture was stirred for an
additional 30 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of bromide anions was
monitored by silver nitrate test. Chloroform was removed on a
rotary evaporator and remaining product was dried removed at
60.degree. C. under vacuum. Product, as viscous liquid, was
obtained in 81.00% yield. .sup.1H and .sup.13C NMR (DMSO) were
obtained. The two ions have known antimicrobial and sweetener
properties, respectively.
Example LXV
Diundecyldimethylammonium Acesulfamate
##STR00308##
[0536] Diundecyldimethylammonium bromide (0.0023 mol) was dissolved
in 7 mL of distilled water by gentle heating and stirring.
Potassium acesulfamate (0.001 mol) was dissolved in 7 mL of
distilled water by gentle heating and stirring. The two solutions
were combined and the reaction mixture was heated and stirred for
90 minutes. The reaction mixture was cooled to room temperature and
then 7 mL of chloroform was added. The reaction mixture was stirred
for an additional 20 minutes. The two phases were separated and the
chloroform phase was washed several times with cool distilled water
to remove any inorganic salt. The presence of bromide anions was
monitored by silver nitrate test. Chloroform was removed on a
rotary evaporator and remaining product was dried removed at
60.degree. C. under vacuum. Product, as viscous liquid, was
obtained in 92% yield. .sup.1H and .sup.13C NMR (DMSO) were
obtained. The two ions have known antimicrobial and sweetener
properties, respectively.
Example LXVI
Didecyldimethylammonium Docusate
[0537] Didecyldimethylammonium bromide (0.005 mol) was dissolved
100 mL of 95% ethanol by gentle stirring. Docusate sodium was
dissolved in 50 mL of 95% ethanol by gentle stirring. The two
solutions were combined and the reaction mixture was stirred for 1
hour at room temperature. A rotary evaporator removed the ethanol
to give the ionic liquid and NaBr. The ionic liquid was dissolved
in hexane and the NaBr was filtered off. A rotary evaporator
removed the hexane to give a white solid obtained in a 78.00%
yield. .sup.1H and .sup.13C NMR (DMSO) were obtained. Melting point
(hot plate apparatus)=25-30.degree. C.
Example LXVII
Lidocaine Docusate Rat Tail Flick Test
[0538] The rat tail flick test is used to determine the local
anesthetic ability of lidocaine docusate compared with lidocaine
hydrochloride. The rat is immobilized in a restraining sock, so
that the tail is only exposed. The tail is dipped into hot water
and the number of times the rat flicks its tail is recorded. When
the anesthetic is applied, the rat's tail should be numb therefore
it will not feel the hot water and the number of tail flicks should
decrease.
[0539] For this test Swiss-Webster male mice were used. They were
habituated in a restraining sock 3 times during a 10 day period. A
baseline tail flick was determined for each rat in 47.5.degree. C.
water bath. The rat's tail was then dipped into a solution of
dimethyl sulfoxide (DMSO) and lidocaine hydrochloride or lidocaine
docusate for 60 seconds. The number of tail flicks was determined
at 15, 30, 60, and 120 minutes in the 47.5.degree. C. water bath.
FIGS. 4A and B are two graphs with the results at concentrations of
DMSO lidocaine hydrochloride solution and lidocaine docusate of 1
mM and 100 mM. Using the following equation, one can determine the
% MPE at each time for the two compounds in question.
%MPE=(TF.sub.i-BL)/(10-BL)*100 [0540] TF.sub.i=latency to withdraw
tail from hot water [0541] BL=baseline withdrawal time without the
drug
[0542] One can see from the graphs that lidocaine docusate has a
higher and longer anesthetic ability than lidocaine hydrochloride
in DMSO. This is likely due to the synergistic effects.
Prophetic Example LXVIII
Hexadecylpyridinium Clofencet, Fluoroxypyr, Diflufenzopyr,
Mesosolfuron, Prohexadione, Pantoprazole, Risedronate, Losartan,
Rabeprazole, Fosinopril, Ceftioxone, Atorvastatin, Pravastatin,
Alendronate, Montelukast, Tazobactam, Allura Red AC, Tartrazine,
Indigotine, Erythrosine, and Sunset Yellow
[0543] (Depending on each compound's solubility, the following
procedure can be alternated to compensate). Hexadecylpyridinium
chloride (0.001 mol) is dissolved in 60 mL of distilled water by
gentle heating and stirring. The anion (0.001 mol) is dissolved in
60 mL of distilled water by gentle heating and stirring. The two
solutions are combined and the reaction mixture is heated and
stirred for 30 minutes. The reaction mixture is cooled to room
temperature and then 60 mL of chloroform is added. The reaction
mixture is stirred for an additional 30 minutes. The two phases are
separated and the chloroform phase is washed several times with
cool distilled water to remove any inorganic salt. The presence of
chloride anions is monitored by silver nitrate test. A rotary
evaporator is used to remove the chloroform and a product will be
obtained. Hot plate apparatus can be used to determine melting
point and percent yield of the compound can be calculated. Also
.sup.1H and .sup.13C NMR and thermalgravimetric analysis can be
performed.
Prophetic Example LXIX
Didecyldimethylammonium Clofencet, Fluoroxypyr, Diflufenzopyr,
Mesosulfuron, Prohexadione, Pantoprazole, Risedronate, Losartan,
Rabeprazole, Fosinopril, Ceftioxone, Atorvastatin, Pravastatin,
Alendronate, Montelokast, Tazobactam, Allura Red AC, Tartrazine,
Indigotine, Erythrosine, and Sunset Yellow
[0544] (Depending on each compound's solubility, the following
procedure can be alternated to compensate). Didecyldimethylammonium
bromide (0.001 mol) is dissolved in 60 mL of distilled water by
gentle heating and stirring. The anion (0.001 mol) is dissolved in
60 mL of distilled water by gentle heating and stirring. The two
solutions are combined and the reaction mixture is heated and
stirred for 30 minutes. The reaction mixture is cooled to room
temperature, and then 60 mL of chloroform is added. The reaction
mixture is stirred for an additional 30 minutes. The two phases are
separated and the chloroform phase is washed several times with
cool distilled water to remove any inorganic salt. The presence of
chloride anions is monitored by silver nitrate test. A rotary
evaporator is used to remove the chloroform and a product will be
obtained. Hot plate apparatus can be used to determine melting
point and percent yield of the compound can be calculated. Also
.sup.1H and .sup.13C NMR and thermalgravimetric analysis can be
performed.
Prophetic Example LXX
Benzalkonium Clofencet, Fluoroxypyr, Diflufenzopyr, Mesosulfuron,
Prohexadione, Pantoprazole, Risedronate, Losartan, Rabeprazole,
Fosinopril, Ceftioxone, Atorvastatin, Pravastatin, Alendronate,
Montelukast, Tazobactam, Allura Red AC, Tartrazine, Indigotine,
Erythrosine, and Sunset Yellow
[0545] (Depending on each compound's solubility, the following
procedure can be alternated to compensate). Benzalkonium chloride
(0.001 mol) is dissolved in 60 mL of distilled water by gentle
heating and stirring. The anion (0.001 mol) is dissolved in 60 mL
of distilled water by gentle heating and stirring. The two
solutions are combined and the reaction mixture is heated and
stirred for 30 minutes. The reaction mixture is cooled to room
temperature and then 60 mL of chloroform is added. The reaction
mixture is stirred for an additional 30 minutes. The two phases are
separated and the chloroform phase is washed several times with
cool distilled water to remove any inorganic salt. The presence of
chloride anions is monitored by silver nitrate test. A rotary
evaporator is used to remove the chloroform and a product will be
obtained. Hot plate apparatus can be used to determine melting
point and percent yield of the compound can be calculated. Also
.sup.1H and .sup.13C NMR and thermalgavimetric analysis can be
performed.
[0546] Other advantages which are obvious and which are inherent to
the invention will be evident to one skilled in the art. It will be
understood that certain features and sub-combinations are of
utility and may be employed without reference to other features and
sub-combinations. This is contemplated by and is within the scope
of the claims. Since many possible embodiments may be made of the
invention without departing from the scope thereof, it is to be
understood that all matter herein set forth or shown in the
accompanying drawings is to be interpreted as illustrative and not
in a limiting sense.
* * * * *